Heteroaryloxy 3-substituted propanamines as serotonin and norepinephrine reuptake inhibitors

ABSTRACT

There is provided a heretoaryloxy 3-substituted propanamine compound of formula (I): wherein A is selected from —O— and —S—; X is selected from phenyl optionally substituted with up to 5 substituents selected from halo, C 1 –C 4  alkyl and C 1 –C 4  alkoxy, and thienyl optionally substituted with up to 3 substituents selected from halo and C 1 –C 4  alkyl; Y is selected from benzothienyl, indolyl and benzofuranyl, optionally substituted with up to 5 substituents selected from halo, C 1 –C 4  alkyl, C 1 –C 4  alkoxy, nitro, acetyl and cyano; and when Y is indolyl it may be substituted or further substituted by an N-substituent selected from C 1 –C 4  alkyl; R 1  and R 2  are each independently H or C 1 –C 4  alkyl; and pharmaceutically acceptable salts thereof.

This application is a §371 of PCT/US02/11874, filed on May 6, 2002.

This invention relates to novel heteroaryloxy 3-substitutedpropanamines, and to their use in inhibiting serotonin andnorepinephrine reuptake.

Serotonin has been implicated in the aetiology of many disease statesand has been found to be of importance in mental illnesses, depression,anxiety, schizophrenia, eating disorders, obsessive compulsive disorder(OCD) and migraine. Indeed many currently used treatments of thesedisorders are thought to act by modulating serotonergic tone. During thelast decade, multiple serotonin receptor subtypes have beencharacterised. This has led to the realisation that many treatments actvia the serotonergic system, such as selective serotonin reuptakeinhibitor (SSRI) antidepressants which increase serotonin transmission,for example, the hydrochloride salt of fluoxetine.

Drugs that exert their main action on the norepinephrinergic system havebeen available for some time, however their lack of selectivity made itdifficult to determine specific clinical effects produced by a selectiveaction on norepinephrine reuptake. Accumulating evidence indicates thatthe norepinephrinergic system modulates drive and energy, whereas theserotonergic system modulates mood. Thus norepinephrine appears to playan important role in the disturbances of vegetative function associatedwith affective, anxiety and cognitive disorders. Atomoxetinehydrochloride is a selective inhibitor of norepinephrine, and iscurrently under development for the treatment of attention deficithyperactivity disorder (ADHD).

Norepinephrine and serotonin receptors are known to interactanatomically and pharmacologically. Compounds that affect only serotoninhave been shown to exhibit modulatory effects on norepinephrine,pointing toward an important relationship between the twoneurotransmitter systems.

Duloxetine, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanaminehydrochloride, inhibits the reuptake of both norepinephrine andserotonin, and is currently under development for the treatment ofdepression and urinary incontinence. The compound duloxetine wasdisclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388.

U.S. Pat. No. 4,018,895 describes aryloxyphenyl propanamine compoundsincluding compunds of the formula

Where R is, for example, phenyl, substituted phenyl, tolyl or anisyl.The compounds block the uptake of various physiologically activemonoamines including serotonin, norepinephrine and dopamine. Some of thecompounds are selective to one of the monoamines and others havemultiple activity. The compounds are indicated as psychotropic agents.Some are also antagonists of apomorphine and/or reserpine.

WO 00/02551 describes compounds which are active at the NMDA receptorand serotonin reuptake site.

WO 97/45115 describes compounds which inhibit glycine transport via theGlyT-1 or GlyT-2 transporters.

WO 96/09288 describes compounds which are active at the 5HT receptor.

The present invention provides novel heteroaryloxy propanamines whichare potent inhibitors of both serotonin and norepinephrine reuptake.

According to the present invention there is provided a compound offormula I:

wherein

-   A is selected from —O— and —S—;-   X is selected from phenyl optionally substituted with up to 5    substituents selected from halo, C₁–C₄ alkyl and C₁–C₄ alkoxy, and    thienyl optionally substituted with up to 3 substituents selected    from halo and C₁–C₄ alkyl;-   Y is selected from benzothienyl, indolyl and benzofuranyl,    optionally substituted with up to 5 substituents selected from halo,    C₁–C₄ alkyl, C₁–C₄ alkoxy, nitro, acetyl and cyano;-   and when Y is indolyl it may be substituted or further substituted    by an N-substituent selected from C₁–C₄ alkyl;-   R₁ and R₂ are each independently H or C₁–C₄ alkyl;-   and pharmaceutically acceptable salts thereof.

A sub-group of compounds acording to the present invention includescompounds of formula I wherein A is —O—;

-   X is selected from phenyl, and thienyl optionally substituted with a    substituent selected from halo and C₁–C₄ alkyl;-   Y is selected from benzothienyl, benzofuranyl and indolyl optionally    substituted with one to three substituents from the groups halo,    C₁–C₄ alkyl, C₁–C₄ alkoxy and cyano;-   R₁ and R₂ are each independently H or C₁–C₃ alkyl;-   and pharmaceutically acceptable salts thereof.

The compounds of the present invention are potent and selectiveinhibitors of serotonin and norepinephrine reuptake.

In one group of compounds according to the present invention, A is —O—.

In another group of compounds according to the present invention, A is—S—.

Preferably, one of R₁ and R₂ is H.

R₁ and R₂ may both be H. Alternatively, one of R₁ and R₂ may be H whilethe other is C₁–C₄ alkyl, for example C₁–C₃ alkyl. When one of R₁ and R₂is C₁–C₄ alkyl, said C₁–C₄ alkyl may be substituted with for example aC₃–C₆ cycloalkyl group. Preferably, the C₁–C₄ alkyl group isunsubstituted. Preferably, one of R₁ and R₂ is H and the other ismethyl.

When X in formula I above is substituted phenyl, it is preferably mono-di- or tri-substituted with halo, C₁–C₄ alkyl and/or C₁–C₄ alkoxy. Halosubstituents include F, Cl, Br and I, preferably F or Cl.

C₁–C₄ alkyl substituents include unsubstituted straight or banched alkylgroups of 1, 2, 3 or 4 carbon atoms, optionally substituted with forexample one or more halogens, for example F. Preferred C₁–C₄ alkylsubstituents include methyl and trifluoromethyl. C₁–C₄ alkoxysubstituents include unsubstituted and substituted alkoxy groups of 1,2, 3, or 4 carbon atoms, linked through the —O— atom; suitablesubstituents include halogens, for example F, as in —OCF₃. A preferredC₁–C₄ alkoxy group is methoxy.

When X in formula I above is substituted thienyl, it is mono-, di- ortri-substituted. Halo substituents include F, Cl, Br and I, preferably For Cl. C₁–C₄ alkyl substituents include unsubstituted straight orbanched alkyl groups of 1, 2, 3 or 4 carbon atoms, and correspondingsubstituted groups—suitable substituents include halogens, for exampleF. Preferred C₁–C₄ alkyl substituents include methyl andtrifluoromethyl. When X is thienyl it is preferably thien-2-yl.

In a preferred embodiment of the present invention, X is phenyl orsubstituted phenyl.

In a particular embodiment of the present invention, Y is indolyl. In apreferred embodiment, Y is benzofuranyl. In another preferredembodiment, Y is benzothienyl. A preferred point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 7-position.Attachment at the 4-position is further preferred. Other points ofattachment, for example 5- and 6- are also possible.

When Y is N-substituted indolyl, the substituent is preferably Me. WhenY is substituted benzothienyl, indolyl (with or without N-substitution)or substituted benzofuranyl, there may be 4 or 5 substituents, but mono-di- or tri-substitution is preferred, for example di-substitution, ormono-substitution. Halo substituents include F, Cl, Br and I, preferablyF or Cl. C₁–C₄ alkyl substituents include unsubstituted straight orbranched alkyl groups of 1, 2, 3 or 4 carbon atoms, and correspondingsubstituted groups—suitable substituents include halogens, for exampleF. Preferred C₁–C₄ alkyl substituents include methyl andtrifluoromethyl.

Especially preferred compounds are those in which X is phenyl and Y isbenzothienyl, particularly halo-substituted benzothienyl and moreparticularly F-substituted benzothienyl; and especially where one of R₁and R₂ is H and the other is Me.

The present invention also provides processes for producing a compoundof formula I above, which comprises reacting a compound of the formulaII:

where A, X and Y are as formula I above, and W is a leaving group, withan alkyl amine. Examples of suitable leaving groups include halo,mesylate and tosylate, but the nature of the leaving group is notcritical. The reaction is carried out in a sealed vessel with a loweralkyl alcohol as solvent.

Compounds of the present invention are selective inhibitors of thereuptake of both serotonin and norepinephrine and as such are useful aspharmaceuticals. They are particularly useful for the treatment of pain.

For clinical purposes, pain may be divided into two categories: acutepain and persistent pain. Acute pain is provoked by noxious stimulationproduced by injury and/or disease of skin, deep somatic structures orviscera, or abnormal function of muscle or viscera that does not produceactual tissue damage. On the other hand, persistent pain can be definedas pain that persists beyond the usual course of an acute disease or areasonable time for an injury to heal or that is associated with achronic pathologic process that causes continuous pain or the painrecurs at intervals for months or years. If pain is still present aftera cure should have been achieved, it is considered persistent pain. Forthe purpose of the present invention, persistent pain can be chronicnon-remitting or recurrent. The difference in definition between acuteand persistent pain is not merely semantic but has an important clinicalrelevance. For example, a simple fracture of the wrist usually remainspainful for a week to 10 days. If the pain is still present beyond thetypical course of treatment, it is likely that the patient is developingreflex sympathetic dystrophy, a persistent pain syndrome that requiresimmediate effective therapy. Early and effective interventionpotentially prevents the undue disability and suffering, and avoids thepotential development of a condition that becomes refractory to therapy.

Acute and chronic pain differ in etiology, mechanisms, pathophysiology,symptomatology, diagnosis, therapy, and physiological responses. Incontrast to the transitory nature of acute pain, persistent pain iscaused by chronic pathologic processes in somatic structures or viscera,by prolonged and sometimes permanent dysfunction of the peripheral orcentral nervous system, or both. Also, persistent pain can sometimes beattributed to psychologic mechanisms and/or environmental factors.

Current therapies for persistent pain include opiates, barbiturate-likedrugs such as thiopental sodium and surgical procedures such asneurectomy, rhizotomy, cordotomy, and cordectomy.

The compounds of the present invention are indicated in the treatment ofpersistant pain and references herein to pain are intended to refer topersistent pain.

In addition to the compounds of formula I and processes for thepreparation of said compounds, the present invention further providespharmaceutical compositions comprising a compound of formula I or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier.

Further, the present invention provides a compound of formula I or apharmaceutically acceptable salt thereof, for use as a pharmaceutical;and a compound of formula I or a pharmaceutically acceptable saltthereof, for use as a selective inhibitor of the reuptake of bothserotonin and norepinephrine.

The present compounds and salts may be indicated in the treatment ofdisorders associated with serotonin and norepinephrine dysfunction inmammals, including depression, OCD, anxiety, memory loss, urinaryincontinence, conduct disorders, ADHD, obesity, alcoholism, smokingcessation and pain. The compounds of the present invention areparticularly suitable for the treatment of pain.

The present invention also provides the use of a compound of formula I,or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament for selectively inhibiting the reuptake of serotonin andnorepinephrine; the use of a compound of formula I, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of disorders associated with serotonin andnorepinephrine dysfunction in mammals; the use of a compound of formulaI, or a pharmaceutically acceptable salt thereof, in the manufacture ofa medicament for the treatment of a disorder selected from depression,OCD, anxiety, memory loss, urinary incontinence, conduct disorders,ADHD, obesity, alcoholism, smoking cessation and pain; and the use of acompound of formula I, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the treatment of a disorder selectedfrom depression, urinary incontinence, particularly stress inducedurinary incontinence, and more especially, pain. The present inventionfurther provides a compound of formula I for treating disordersassociated with serotonin and norepinephrine dysfunction in mammals, forexample a disorder selected from depression, OCD, anxiety, memory loss,urinary incontinence, conduct disorders, ADHD, obesity, alcoholism,smoking cessation and pain, especially depression, urinary incontinence,particularly stress induced urinary incontinence, and, more especially,pain.

Further the present invention provides a method for selectivelyinhibiting the reuptake of serotonin and norepinephrine in mammals,comprising administering to a patient in need thereof an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof; a method for treating disorders associated with serotonin andnorepinephrine dysfunction in mammals, comprising administering to apatient in need thereof an effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof; and a method for treatinga disorder selected from depression, OCD, anxiety, memory loss, urinaryincontinence, conduct disorders, ADHD, obesity, alcoholism, smokingcessation and pain, comprising administering to a patient in needthereof an effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

The term C₁–C₃ alkyl herein represents a straight or branched alkylchain bearing from one to three carbon atoms. C₁–C₄ alkyl represents astraight or branched alkyl chain bearing from one to four carbon atoms.Typical C₁–C₃ alkyl groups include methyl, ethyl, n-propyl andisopropyl. Typical C₁–C₄ alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl and t-butyl. A C₁–C₄ alkoxy group is a C₁–C₄ alkylgroup linked through oxygen to the heterocyclic nucleus. The term halorepresents any of the groups fluoro, chloro, bromo and iodo. When X isthienyl it can be either 2-thienyl or 3-thienyl. The terms alkyl andalkoxy may include substituted alkyl and alkoxy groups, particularlyhalo-substituted, for example F-substituted groups.

The present invention includes the pharmaceutically acceptable salts ofthe compounds of formula I. Suitable salts include acid addition salts,including salts formed with inorganic acids, for example hydrochloric,hydrobromic, nitric, sulphuric or phosphoric acids, or with organicacids, such as organic carboxylic acids, for example pyruvic,lactobionic, glycolic, oxalic, maleic, hydroxymaleic, fumaric, malic,tartaric, citric, salicylic, o-acetoxybenzoic, or organic sulphonic,2-hydroxyethane sulphonic, toluene-p-sulphonic, bisethanesulphonic acidor methanesulphonic acid.

In addition to the pharmaceutically acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of compounds or in the preparation of other, for examplepharmaceutically acceptable, acid addition salts, or are useful foridentification, characterisation or purification.

While all the compounds of the present invention are believed to inhibitthe reuptake of serotonin and norepinephrine in mammals there arecertain of these compounds which are preferred for such uses. Preferredvalues for X, Y, R₁ and R₂ and substituents for each have been set outabove.

Other compounds include compounds of formula I when A is —O— and subjectto one or more of the following:

-   when X is substituted thienyl it is preferably substituted with Cl    or Me, most preferably in the 5 position;-   when Y is 1-benzothienyl it is preferably 1-benzothien-7-yl or    1-benzothien-4-yl; when Y is indolyl it is preferably indol-7-yl or    indol-4-yl;-   when Y is 1-benzothien-7-yl, or indol-7-yl optionally substituted    with one to three substituents including substituents from the    groups halo, C₁–C₄ alkyl, C₁–C₄ alkoxy and cyano, the respective    groups are preferably in the 2, 3 and/or 4 positions; when Y is    1-benzothien-4-yl or indol-4-yl optionally substituted with one to    three substituents including substituents from the groups halo,    C₁–C₄ alkyl, C₁–C₄ alkoxy and cyano, the respective groups are    preferably in the 2, 3 and/or 7 positions;-   when Y is substituted 1-benzothienyl, 1-benzofuranyl or indolyl it    is preferably substituted with one to three substituents from the    groups fluorine, chlorine, methyl, methoxy and cyano, more    preferably fluorine, chlorine and methyl; more preferably, both X    and Y are unsubstituted;-   preferably, one of R₁ and R₂ is methyl; more preferably, one of R₁    and R₂ is hydrogen and the other is methyl.

It will be appreciated that compounds of formula I possess an asymmetriccarbon atom, and that they exist in the form of individualstereoisomers, as well as the racemic mixture. When the stereoisomericform of a compound is not indicated in this document, it will beunderstood that both of the possible isomeric forms, as well as theracemate, are intended. When an individual stereoisomer is indicated,the isomeric form will be stated as part of the name.

Compounds of the present invention may be prepared by conventionalorganic chemistry techniques. For example, where X is phenyl the chiralalcohols are commercially available from the Aldrich Chemical Company inpure enantiomeric form and can be used without further purification.

Additionally, the chloropropanols which are commercially available fromthe Aldrich Chemical Company may be converted via a Finkelstein reactionusing sodium iodide in acetone under reflux conditions to thecorresponding iodopropanols and these may be used as an alternative tothe chloropropanols.

Where X is thienyl the corresponding thienyl-propanols can typically beprepared generally as follows (W is as defined above):

Subjecting thiophene to classical Friedel-Crafts acylation with an acidchloride such as chloropropionyl chloride in roughly equal quantities,with a strong Lewis acid such as aluminium chloride in a non-proticsolvent such as dichloromethane or dichloroethane at temperaturesranging from −5° C. to reflux can result in the desired thienyl ketone.This ketone can be readily reduced to the desired alcohol eitherracemically using standard reducing agents such as sodium borohydride ina protic solvent such as the lower order alkyl alcohols, or Borane-THFcomplex in a polar non-protic solvent such as diethyl ether or THF.Chiral reduction of the ketone can be performed using a boron basedchiral reducing agent in which high enantiomeric excesses can beobtained. Further details regarding this procedure can be found in J.Labelled Compd. Rad., 1995, 36, (3), 213 and references therein.

The benzothiophenes of the invention have been made by several routes.Thus a preferred route is by the alkylation of a thiophenol derivativewith bromoacetaldehyde diethyl acetal followed by subsequent acidcatalysed cyclisation with polyphosphoric acid in chlorobenzene withelimination of ethanol. Subsequent demethylation provided thehydroxybenzothiophene needed for subsequent ether formation.

Analogous cyclisation of phenylthioacetone derivatives with PPA can beused to synthesise 3-methyl derivatives of benzothiophene methyl ethers

A further preferred route to substituted benzothiophenes is an iodinecatalysed cyclisation of a mercaptopropenoic acid. Thus a benzaldehydecan be condensed with rhodanine and subsequently hydrolysed under basicconditions to a mercaptopropenoic acid. The resultant mercaptopropenoicacid can be cyclised using iodine and then decarboxylated withdiazobicycloundecane in dimethylacetamide. Finally boron tribromide indichloromethane may be used to demethylate the methyl ether to providethe hydroxybenzothiophene.

Where X is thienyl or phenyl the corresponding ethers can typically beprepared generally as follows (W and Y are as defined above).

The chiral hydroxy intermediates can then be subjected to alkylationreactions. Various alkylation conditions can be used such as theMitsunobu reaction, wherein roughly equal quantities of the heteroarylalcohol phenol) and chloropropanol or iodopropanol are stirred attemperatures of between 0° C. and reflux in a polar non-protic solventsuch as THF, with a complexing agent such as diethyl azodicarboxylate,or other derivative with a phosphine ligand such as triphenylphosphine.Alternatively4,4-(dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium in THF may be used in place of mixtures diethylazodicarboxylate and triphenylphosphine. This type of reaction is wellknown and further combinations of the Mitsunobu reagents can be found inOrganic Preparations and Procedures Int., 1996, 28, 2, 165 andreferences therein.

The corresponding ethers can be readily converted to the amines byheating in a sealed vessel with the appropriate alkyl amine in a loweralkyl alcohol solvent, at temperatures between 100° C. and 150° C. forbetween 1 and 6 hours. To aid handling of the resulting amines theirorganic acid salts can typically be prepared using equimolar quantitiesof the propanolamines with an organic acid such as oxalic and maleicacid. The reactants are generally combined in a mutual solvent such asethyl acetate, and the salt normally precipitates out over time and canbe isolated by filtration, or by removing the solvent in vacuo,re-dissolving in purified water and freeze drying to obtain the salt.

Compounds of formula I where R₁=methyl and R₂=H may be prepared by solidphase synthesis by the route shown below.

The sequence is preferably performed on a macroporous polystyrene resin,e.g. Thus ArgoPore-Cl is converted with methylamine in methanol to asecondary amine bound to the resin. A Mannich type reaction is thenperformed on the resin bound amine with aqueous formaldehyde,hydrochloric acid a substituted acetophenone and isopropanol. Theresultant aminoketone is then reduced with sodium borohydride inethanol/triethyleneglycol dimethyl ether to give the amino alcohol. Thisis then subjected to a Mitsunobu reaction usingdi-t-butylazodicarboxylate, triphenyl phosphine and a heterocyclicphenol to give a resin bound heteroaryl aminoether. Removal of theaminoether from the resin is effected with 1-chloroethyl chloroformateand Hunigs base in THF. Finally resolution of the enantiomers isachieved using chiral chromatography.

The following Examples further illustrate the compounds of the presentinvention and methods for their synthesis.

In the following section, there is described the synthesis of precursorsand common intermediates for the compounds of the present invention.

4-Fluoro-2-methoxybenzenethiol

a) 2-Bromo-5-fluoroanisole

To a suspension of 2-bromo-5-fluorophenol (20.0 g, 104.7 mmol) andpotassium carbonate (21.71 g, 157.1 mmol) in acetone (200 mL) was addeddimethyl sulphate (10.90 mL, 115.2 mmol). The resulting suspension wasallowed to stir at 60° C. for 2 h before being allowed to cool and thenconcentrated in vacuo. The residue was dissolved in ether (200 mL) andwater (100 mL). The organic phase was washed with aqueous hydrochloricacid (2 N, 50 mL), saturated sodium bicarbonate solution (50 mL) withthe resulting organic phase being dried (MgSO₄) and the solventevaporated in vacuo to give a pale yellow oil (21.46 g, 100%). δ_(H)(300 MHz, CDCl₃) 7.45 (1H, dd, Ar), 6.70–6.55 (2H, m, Ar), 3.90 (3H, s,OCH₃).

b) 4-Fluoro-2-methoxybenzenethiol

To a suspension of 2-bromo-5-fluoroanisole (2.00 g, 9.755 mmol) andelemental sulphur (0.468 g, 14.632 mmol) in dry THF (50 mL) was slowlyadded tert-butyl lithium in pentane (1.7 M, 12.6 mL, 21.46 mmol) at −78°C. The resulting suspension was allowed to stir at −78° C. for 60 minsbefore being poured onto saturated ammonium chloride solution (80 mL)and product extracted with diethyl ether (100 mL). The organic phase waswashed with aqueous hydrochloric acid (2 N, 40 mL), with the resultingorganic phase being dried (MgSO₄) and the solvent evaporated in vacuo togive a pale yellow oil. This was treated to a pad of silica gel, elutingwith hexane:ethyl acetate [95:5] to give a pale yellow oil (1.50 g,68%). δ_(H) (300 MHz, CDCl₃) 7.20 (1H, dd, Ar), 6.65–6.55 (2H, d, Ar),3.90 (3H, s, OCH₃), 3.68 (1H, s, SH).

Similarly prepared was

3-Methoxy-5-trifluoromethylbenzenethiol as a pale yellow oil (14.473 g,100%). δ_(H) (300 MHz, CDCl₃) 7.40–6.90 (3H, m, Ar), 3.87 (1H, s, SH),3.80 (3H, s, OCH₃).

3-Fluoro-2-methoxybenzaldehyde

To a suspension of 3-fluoro-2-hydroxybenzaldehyde (5.328 g, 38.02 mmol)and potassium carbonate (7.88 g, 57.03 mmol) in acetone (60 mL) wasadded dimethyl sulphate (3.96 mL, 41.83 mmol). The resulting suspensionwas stirred at 60° C. for 2 h before being allowed to cool and thenconcentrated in vacuo. The residue was dissolved in dichloromethane (100mL) and water (50 mL). The organic phase was washed with saturatedsodium bicarbonate (50 mL) with the resulting organic phase being dried(MgSO₄) and the solvent evaporated in vacuo to give a pale yellow oil(6.262 g, 38.02 mmol, 100%). δ_(H) (300 MHz, CDCl₃) 10.40 (1H, s, CHO),7.60 (1H, d, Ar), 7.30 (1H), m, Ar), 7.10 (1H, m, Ar), 4.10 (3H, s,OCH₃).

5-Methoxy-2-methylbenzaldehyde

a) 4-Bromo-3-(1,3-dioxolan-2-yl)phenyl methyl ether

A solution of 2-bromo-5-methoxybenzaldehyde (10.00 g, 46.5 mmol) intoluene (600 mL), ethanediol (3.88 mL, 69.8 mmol) and para-toluenesulphonic acid (50 mg) were heated under Dean-Stark conditions for 24 h.After this time the reaction was allowed to cool to room temperaturebefore being washed with saturated aqueous sodium hydrogen carbonate(2×150 mL). The organic phase was dried (MgSO₄) and the solvent removedin vacuo to give a colourless oil (12.6 g, 100%); R_(f)=0.23 inhexane:ethyl acetate [10:1]; δ_(H) (300 MHz, CDCl₃) 7.42 (1H, d, Ar),7.25 (1H, d, Ar), 6.75 (1H, dd, Ar), 6.03 (1H, s, CHO), 4.20–4.01 (4H,m, 2×CH₂), 3.80 (3H, s, OCH₃).

b) 3-(1,3-Dioxolan-2-yl)-4-methylphenyl methyl ether

n-Butyl lithium in hexane (17.07 mL, 1.42 M, 25.1 mmol) was addeddropwise at −78° C. to a stirred solution of4-bromo-3-(1,3-dioxolan-2-yl)phenyl methyl ether (5.00 g, 19.3 mmol) indry THF (60 mL). The resulting solution was allowed to stir at −78° C.for 30 mins before being quenched with iodomethane (2.40 mL, 38.6 mmol).The resulting solution was stirred at −78° C. for a further 20 minsbefore being quenched with saturated aqueous ammonium chloride solution(60 mL). The organic phase was dried (MgSO₄) and the solvent evaporatedin vacuo. The residue was purified by flash chromatography elutingsilica gel with hexane:ethyl acetate [10:1] to give a pale yellow oil(3.07 g, 82%); R_(f)=0.40 in hexane:ethyl acetate [10:1]; δ_(H) (300MHz, CDCl₃) 7.20–6.99 (2H, m, Ar), 6.75 (1H, dd, Ar), 5.92 (1H, s, CH),4.20–4.01 (4H, m, 2×CH₂), 3.80 (3H, s, OCH₃), 2.32 (3H, s, CH₃).

c) 5-Methoxy-2-methylbenzaldehyde

A solution of 2-(2-methyl-5-methoxyphenyl)-1,3-dioxalone (7.28 g, 37.5mmol) in THF (1200 mL) and HCl (5%, 50 mL) was stirred at roomtemperature for 48 h. After this time the reaction was diluted withdiethyl ether (100 mL) and washed with brine. The organic phase wasdried (MgSO₄) and the solvent evaporated in vacuo. The residue waspurified by flash chromatography eluting silica gel with hexane:ethylacetate [95:5] to give a pale yellow oil (4.93 g, 88%); R_(f)=0.31 inhexane:ethyl acetate [10:1]; δ_(H) (300 MHz, CDCl₃) 10.28 (1H, s, CHO),7.35–6.99 (3H, m, Ar), 3.82 (3H, s, OCH₃), 2.62 (3H, s, CH₃).

1-[(5-Fluoro-2-methoxyphenyl)thio]acetone

tert-Butyl lithium in pentane (6.30 mL, 10.7 mmol) was added dropwise at−78° C. over 35 mins to a stirred suspension of 2-bromo-4-fluoroanisole(1.00 g, 4.87 mmol) and elemental sulfur (234 mg, 7.31 mmol) in dry THF(10 mL). The resulting yellow solution was stirred and −78° C. for 15mins before chloroacetone (894 mg, 9.74 mmol) was added. The resultingsolution was allowed to stir at −78° C. for 1 hr before being quenchedwith NH₄Cl (sat., 20 mL). The organic phase was extracted and dried(MgSO₄) and the solvent removed in vacuo. The residue was purified byflash chromatography eluting silica gel with hexane:ethyl acetate [4:1]to yield a colourless oil (1.03 g, 98%) which slowly solidified onstanding; R_(f)=0.34 in hexane:ethyl acetate [4:1]; δ_(H) (300 MHz,CDCl₃) 7.08–6.98 (1H, dd, Ar), 6.95–6.82 (1H, m, Ar), 6.80–6.71 (1H, dd,Ar), 3.91 (3H, s, OCH₃), 3.75 (2H, s, CH₂), 2.30 (3H, s, CH₃).

1-[(2-Fluoro-5-methoxyphenyl)thio]acetone

To a solution of 2,2,6,6-tetramethylpiperidine (8.03 mL, 47.6 mmol) inTHF (20 mL) at −78° C. was added a solution of 2.5 M n-butyllithium inhexanes (19.04 mL, 47.6 mmol). After stirring for 30 minutes at −78° C.a solution of 4-fluoroanisole (5 g, 39.7 mmol) in THF (10 mL) was addeddropwise. After a further 30 minutes elemental sulphur (1.78 g, 55.5mmol) was added and stirred until almost all of the sulphur hasdisappeared. Chloroacetone (3.79 mL, 47.6 mmol) was then added and thesolution warmed to room temperature over 2 hours. The reaction wasquenched by pouring into saturated ammonium chloride (50 mL) andextraction with diethyl ether (2×50 mL). The combined organic extractswere dried (MgSO₄) and the solvent removed in vacuo to give a brown oilwhich was purified by flash chromatography with a gradient of 0–5%diethyl ether in hexane to give the title compound (1.96 g, 23%); δ_(H)(300 MHz, CDCl₃) 7.02–6.86 (2H, m, ArH), 6.80–6.71 (1H, m, ArH), 3.78(3H, s, OCH₃), 3.68 (2H, s, CH₂) and 2.29 (3H, s, CH₃).

(S)-(−)-3-Iodo-1-phenyl-1-propanol

To a solution of (S)-(−)-3-chloro-1-phenyl-1-propanol (5 g, 29.3 mmol)in acetone (50 mL) was added sodium iodide (4.83 g, 32.2 mmol). Theresulting solution was heated at reflux for 16 h. The solution wascooled, filtered and concentrated in vacuo. The residue was purified byflash chromatography eluting silica gel with hexane:ethyl acetate [100:0to 3:1] to yield the iodo compound (7.44 g, 97%); δ_(H) (300 MHz, CDCl₃)7.36 (5H, m, Ar), 4.83 (1H, m, O—CH), 3.34–3.15 (2H, m, CH₂), 2.28–2.15(2H, m, CH₂).

(R)-(+)-3-Iodo-1-phenyl-1-propanol

To a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (5 g, 29.3 mmol)in acetone (50 mL) was added sodium iodide (4.83 g, 32.2 mmol). Theresulting solution was heated at reflux for 16 h. The solution wascooled, filtered and concentrated in vacuo. The residue was purified byflash chromatography eluting silica gel with hexane:ethyl acetate [100:0to 3:1] to yield the title compound as a white solid (7.51 g, 98%);δ_(H) (300 MHz, CDCl₃) 7.36 (5H, m, Ar), 4.83 (1H, m, O—CH), 3.34–3.15(2H, m, CH₂), 2.28–2.15 (2H, m, CH₂).

1-Benzothien-7-yl methyl ether

a) 1-[(2,2-Diethoxyethyl)thio]-2-methoxybenzene

To a suspension of 2-methoxybenzenethiol (10 g, 71.4 mmol) and potassiumcarbonate (20 g, 143 mmol) in dry N,N-dimethylformamide (100 mL) wasadded dropwise over 20 mins a solution of bromoacetaldehyde diethylacetal (10.3 mL, 71.4 mmol) in dry N,N-dimethylformamide (50 mL). Theresulting suspension was allowed to stir at room temperature for 45 minsbefore being diluted with water (500 mL) and extracted with hexane (200mL). The organic phase was further extracted with brine (4×100 mL), withthe resulting organic phase being dried (MgSO₄) and the solvent removedin vacuo to give a pale yellow oil (18.6 g) which was ca 95% pure. Thismaterial was further purified by flash chromatography eluting silica gelwith hexane:ether [10:1] to give a colourless oil (18 g, 98%). δ_(H)(300 MHz, CDCl₃) 7.34 (1H, d, Ar), 7.2 (1H, m, Ar), 6.92–6.80 (2H, m,Ar), 4.62 (1H, t, J=7 Hz, CH(OEt)₂), 3.85 (3H, s, OCH₃), 3.70–3.42 (4H,m, OCH₂CH₃), 3.10 (2H, d, J=7 Hz, SCH₂), 1.12 (6H, t, J=7 Hz, OCH₂CH₃).

Similarly prepared were

1-[(2,2-Diethoxyethyl)thio]-4-fluoro-2-methoxybenzene as a colourlessoil (0.828 g, 3.018 mmol, 46%). δ_(H) (300 MHz, CDCl₃) 7.38 (1H, dd,Ar), 6.90 (2H, m, Ar), 4.62 (1H, t, J=7 Hz, CH(OEt)₂), 3.85 (3H, s,OCH₃), 3.70–3.45 (4H, m, OCH₂CH₃), 3.00 (2H, d, J=7 Hz, SCH₂), 1.18 (6H,t, J=7 Hz, OCH₂CH₃).

1-[(2,2-Diethoxyethyl)thio]-3-methoxy-5-trifluoromethylbenzene as a paleorange oil (6.87 g, 21.18 mmol, 34%). δ_(H) (300 MHz, CDCl₃) 7.20 (1H,s, Ar), 7.00 (1H, s, Ar), 6.90 (1H, s, Ar), 4.65 (1H, t, J=7 Hz,CH(OEt)₂), 3.80 (3H, s, OCH₃), 3.70–3.50 (4H, m, OCH₂CH₃), 3.15 (2H, d,J=7 Hz, SCH₂), 1.20 (6H, t, J=7 Hz, OCH₂CH₃).

b) 1-Benzothien-7-yl methyl ether

A solution of 1-[(2,2-diethoxyethyl)thio]-2-methoxybenzene (18 g, 70.3mmol) in dry chlorobenzene (100 mL) was added slowly to a stirredsolution of polyphosphoric acid (50 g) in dry chlorobenzene (300 mL) at145° C. After addition was complete the resulting black solution wasstirred at 155° C. for a further 18 hrs. After this time the reactionwas allowed to cool to room temperature before being filtered through apad of CELITE™, the solid cake was washed with dichloromethane (200 mL)and the combined organic extracts were concentrated in vacuo. Theresidue was purified by flash chromatography eluting silica gel withhexane:ethyl acetate [95:5] to give a pale yellow oil (8.7 g, 75%);δ_(H) (300 MHz, CDCl₃) 7.45–7.29 (4H, m, Ar), 6.75 (1H, d, Ar), 4.00(3H, s, OCH₃).

Similarly prepared were

5-Fluoro-1-benzothien-7-yl methyl ether as a pale yellow oil (0.132 g,0.724 mmol, 24%); δ_(H) (300 MHz, CDCl₃) 7.50 (1H, d, Ar), 7.28 (1H, d,Ar), 7.10 (1H, d, Ar), 6.58 (1H, d, Ar), 4.00 (3H, s, OCH₃).

4-Trifluoromethyl-1-benzothien-6-yl methyl ether as a yellow oil (2.832g,12.19 mmol, 58%); δ_(H) (300 MHz, CDCl₃) 7.50–7.35 (3H, m, Ar), 7.28(1H, s, Ar), 3.90 (3H, s, OCH₃).

4-Fluoro-7-methoxy-1-benzothiophene

a) 5-(2-Fluoro-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one

To a suspension of 2-fluoro-5-methoxybenzaldehyde (5.00 g, 32.46 mmol)and rhodanine (4.31 g, 32.46 mmol) in dry toluene (1000 mL) was addedammonium acetate (50 mg) and acetic acid (2 mL). The resultingsuspension was allowed to stir at 120° C. for 12 h under Dean-Starkapparatus before being allowed to cool and filtered. Resultant solid waswashed with hexane and allowed to dry in vacuo to give an orangecrystalline solid (8.00 g, 91%); δ_(H) (300 MHz, CDCl₃) 7.50 (1H, s,CH═C); 7.31 (1H, t, Ar), 7.20–7.11 (1H, m, Ar), 6.95–6.89 (1H, m, Ar),3.80 (3H, s, OCH₃).

Similarly prepared were

5-(3-Fluoro-2-methoxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one as anorange solid (7.942 g, 78%). δ_(H) (300 MHz, CDCl₃) 7.82 (1H, s,ArCHCR₂), 7.30–7.10 (3H, m, Ar), 4.05 (3H, s, OCH₃).

5-(2-Methyl-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one as anorange crystalline solid (8.00 g, 91%); δ_(H) (300 MHz, CDCl₃) 7.80 (1H,s, Ar), 7.29–7.10 (1H, m, Ar), 6.95–6.84 (2H, m, Ar and CH═C), 3.83 (3H,s, OCH₃), 2.37 (3H, s, CH₃).

b) (2Z)-3-(2-Fluoro-5-methoxyphenyl)-2-mercapto-2-propenoic acid

5-(2-Fluoro-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one (8.00g, 9.7 mmol) was added in one portion to 25% w/v sodium hydroxidesolution (40 mL). This was allowed stir at reflux for 1 h. After thistime the reaction was allowed to cool to room temperature and pouredonto water (50 mL). This was washed with dichloromethane (50 mL), andthe aqueous layer acidified to pH 2 with aqueous hydrochloric acid (2 N,50 mL) to give a white suspension. Product was extracted with ether(2×60 mL), dried (MgSO₄) and solvent removed in vacuo to give a whitesolid (6.71 g, 100%); δ_(H) (300 MHz, CD₃OD) 7.85 (1H, s, Ar), 7.46–7.35(1H, m, Ar), 7.11 (1H, t, Ar), 7.01–6.75 (2H, m, CH═, and SH), 3.80 (3H,s, OCH₃).

Similarly prepared were

(2Z)-3-(3-Fluoro-2-methoxyphenyl)-2-mercapto-2-propenoic acid as a solid(1.596 g, 94%); δ_(H) (300 MHz, CDCl₃) 8.12 (1H, s, ArCHCR₂), 7.60 (1H,d, Ar), 7.15–7.00 (2H, m, Ar), 4.55 (1H, s, SH), 3.98 (3H, s, OCH₃).

(2Z)-3-(2-Methyl-5-methoxyphenyl)-2-mercapto-2-propenoic acid as a whitesolid (6.71 g 100%); δ_(H) (300 MHz, CDCl₃) 8.00 (1H, s, CH═C),7.30–7.09 (2H, m, Ar), 6.88–6.78 (1H, m, Ar), 3.80 (3H, s, OCH₃), 2.25(3H, s, CH₃).

c) 4-Fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid

(2Z)-3-(2-Fluoro-5-methoxyphenyl)-2-mercapto-2-propenoic acid (1.00 g,4.38 mmol) was added in one portion to a solution of iodine (1.66 g,6.56 mmol) in dimethoxyethane (10 mL). This was heated in the microwavewith 300 W at 160° C. for 10 mins. After this time the reaction wasallowed to cool to room temperature and poured onto saturated sodiummetabisulphite (200 mL) and ether (400 mL). Ether layer was separatedand product extracted with aqueous sodium hydroxide (2 N, 2×100 mL).This was then acidified to pH 2 with aqueous hydrochloric acid (2 N, 250mL), and product extracted with ether (2×150 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to give a whitesolid (580 mg, 30%); δ_(H) (300 MHz, CD₃OD) 8.00 (1H, s, Ar), 7.30–7.19(1H, m, Ar), 7.10–7.00 (1H, m, Ar), 3.95 (3H, s, OCH₃).

Similarly prepared was

4-Methyl-7-methoxy-1-benzothiophene-2-carboxylic acid as white solid(580 mg, 30%); δ_(H) (300 MHz, CDCl₃) 8.20 (1H, s, Ar), 7.12 (1H, d,Ar), 6.75 (1H, d, Ar), 3.99 (3H, s, OCH₃), 2.59 (3H, s, CH₃).

d) 4-Fluoro-7-methoxy-1-benzothiophene

4-Fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (2.00 g, 8.84mmol) was added in one portion to DBU (8 mL) and dimethyl acetamide (10mL). This was heated in the microwave with 300 W at 200° C. for 1 h. Thereaction mixture was allowed to cool and poured onto water (100 mL).Product was extracted with hexane (2×100 mL), washed with aqueoushydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N, 50 mL),and the combined organic extracts were dried (MgSO₄) and concentrated invacuo. The residue was purified by flash chromatography eluting silicagel with hexane:ethyl acetate [96:4] to give an oil (1.12 g, 70%); δ_(H)(300 MHz, CDCl₃) 7.4 (2H, s, Ar), 6.9 (1H, t, Ar), 6.60 (1H, dd, Ar),3.91 (3H, s, OCH₃).

Similarly prepared was

4-Methyl-7-methoxy-1-benzothiophene as an oil (1.12 g, 70%); δ_(H) (300MHz, CDCl₃) 7.46–7.32 (2H, m, Ar), 7.10 (1H, d, Ar), 6.66 (1H, d, Ar),3.98 (3H, s, OCH₃), 2.52 (3H, s, CH₃).

5-Fluoro-4-methoxy-1-benzothiophene

(2Z)-3-(3-Fluoro-2-methoxyphenyl)-2-mercapto-2-propenoic acid (4.865 g,21.315 mmol) was added in one portion to a solution of iodine (8.255 g,31.973 mmol) in dimethoxyetheane (30 mL). This was heated in themicrowave with 300 W at 120° C. for 25 mins. After this time thereaction was allowed to cool to room temperature and poured ontosaturated sodium metabisulphite (200 mL) and ether (400 mL). Ether layerwas separated and product extracted with aqueous sodium hydroxide (2 N,2×100 mL). This was then acidified to pH 2 with aqueous hydrochloricacid (2 N, 250 mL), and product extracted with ether (2×150 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto give a tan coloured solid (3.240 g, 14.322 mmol, 67%). Which was usedwithout further purification in the next step.5-Fluoro-4-methoxy-1-benzothiophene-2-carboxylic acid (0.883 g, 3.903mmol) was added in one portion to DBU (2.04 mL, 13.661 mmol) anddimethyl acetamide (10 mL). This was heated in the microwave with 300 Wat 200° C. for 1 h. Reaction was allowed to cool and poured onto water(100 mL). Product was extracted with hexane (2×100 mL), washed withaqueous hydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N,50 mL), and the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyeluting silica gel with hexane:ethyl acetate [96:4] to give a paleyellow oil (0.167 g, 23%); δ_(H) (300 MHz, CDCl₃) 7.60–6.80 (4H, m, Ar),4.10 (3H, s, OCH₃).

7-Fluoro-4-methoxy-1-benzothiophene

a) 2-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-N,N-dimethylethanethioamide

To a solution of lithium diisopropylamide, 2M in THF/n-heptane (210 mL,583 mmol) was added THF (100 mL) and the solution cooled to −78° C.under nitrogen. This was then added dropwise over 1 h to a solution ofthe 5-fluoro-2-methoxybenzaldehyde (50 g, 0.32 mmol) andN,N-dimethylthioformamide (34.7 g, 389 mmol) in dry THF (200 mL). Thiswas warmed to −5° C. and quenched with water (400 mL). The solution wasfiltered and washed with diethyl ether, the aqueous layer was extractedwith ether (1 L). The combined organic layers were washed with water(500 mL), dried (MgSO₄) and the solvent removed in vacuo to give acrystalline suspension in oil. This was triturated in ether and filteredto give a crystalline solid (21.8 g, 28%); δ_(H) (300 MHz, CDCl₃)7.16–6.81 (3H, m, ArH), 5.81–5.75 (1H, m, CHOH), 5.31–5.22 (1H, m, OH),4.89 (3H, s, OCH₃), 3.50 (3H, s, N(CH₃)₂) and 3.08 (3H, s, N(CH₃)₂).

b) N-(7-Fluoro-4-methoxy-1-benzothien-2-yl)-N,N-dimethylamine

A solution of2-(5-fluoro-2-methoxyphenyl)-2-hydroxy-N,N-dimethylethanethioamide (0.5g, 2.1 mmol) in Eaton's reagent (5 mL) were combined and heated rapidlyto 60° C. and left for 1 h. After cooling to room temperature over 2hours the mixture was dropwise addition into prechilled aqueous sodiumhydroxide (2 N, 16.25 mL) with constant stirring. This solution was thenextracted with methyl tert-butyl ether (5×20 mL) and the combinedorganic extracts were dried (MgSO₄) and the solvent removed in vacuo togive a yellow solid. This was purified by flash chromatography with agradient of 0–2% diethyl ether in hexane and gave 0.2 g of yellow solidcontaining an impurity, this was triturated with hexane to leave acolourless solid (0.155 g, 34%) of the title compound; δ_(H) (300 MHz,CDCl₃) 6.70–6.52 (2H, m, ArH), 6.12–6.10 (1H, m, ArH) 3.90 (3H, s, OCH₃)and 3.2 (6H, s, N(CH₃)₂), M+H=226.1.

c) 7-Fluoro-4-methoxy-1-benzothiophen-2(3H)-one

To a solution ofN-(7-fluoro-4-methoxy-1-benzothien-2-yl)-N,N-dimethylamine (1.73 g, 7.7mmol) in THF (25 mL) was added aqueous hydrochloric acid (1 N, 25 mL)and this was heated to 80° C. for 3 h. After cooling to room temperaturethen extracted with ether (100 mL), dried (MgSO₄) and the solventevaporated in vacuo to give a yellow solid. The residue was purified byflash chromatography in 5% ethyl acetate in hexane to give (1.3 g, 84%)of the title compound; δ_(H) (300 MHz, CHCl₃) 6.97–6.87 (1H, m, ArH),6.62–6.55 (1H, m, ArH), 3.91 (2H, s, CH₂) and 3.85 (3H, s, OCH₃).

d) 7-Fluoro-4-methoxy-1-benzothiophene

To a solution of 7-fluoro-4-methoxy-1-benzothiophen-2(3H)-one (1.06, 5.4mmol) in dichloromethane (10 mL) at 0° C. was added slowly a solution ofdiisobutylaluminium hydride in dichloromethane (1 M, 8.04 mL, 8.0 mmol).After 30 mins the reaction was quenched by careful addition of aqueoushydrochloric acid (6 N, 25 mL). The mixture was concentrated to removethe dichloromethane, the aqueous residue was then stirred at 35° C. for2 h. The aqueous solution was extracted with diethyl ether (3×50 mL),washed with aqueous sodium hydroxide (2 N, 50 mL), brine (50 mL) thendried (MgSO₄) and the solvent evaporated in vacuo to give the titlecompound (0.86 g, 87%) as a purple oil; δ_(H) 7.44–7.38 (1H, m, ArH),7.36–7.24 (1H, m, ArH), 6.88–6.80 (1H, m, ArH), 6.57–6.49 (1H, m, ArH)and 3.82 (3H, s, OCH₃).

7-Fluoro-4-methoxy-1-benzothiophene

a) 2,3-Difluoro-6-methoxybenzaldehyde

A solution of lithium diisopropylamide, 2M in THF/n-heptane (171 mL, 341mmol) was further diluted with dry THF (250 mL) and cooled undernitrogen to −75° C. 3,4-Difluoroanisole (46.8 g, 325 mmol) in dry THF(100 mL) was added dropwise and the mixture stirred at −75° C. for 1 h.Dry N,N-dimethylformamide (27.6 mL, 358 mmol) was added dropwise and themixture stirred for 10 mins at −70° C. Acetic acid (30 mL) and water(400 mL) were added, warming the temperature to 10° C. Extracted intodiethyl ether (2×300 mL). Combined extracts were washed with water (250mL), aqueous hydrochloric acid (0.2 N, 400 mL) and brine (2×250 mL),dried (MgSO₄) and the solvent evaporated in vacuo to give a red/orangeoil which crystallised. Purification was by recrystallisation fromdiethyl ether/petroleum ether 40–60 to give (53.0 g, 95%) of solid;δ_(H) (300 MHz, CDCl₃) 10.40 (1H, s, CHO), 7.37 (1H, q, ArH), 6.71 (1H,m, ArH), and 3.93 (3H, s OCH₃).

b) Methyl 7-fluoro-4-methoxy-1-benzothiophene-2-carboxylate

Methyl thioglycolate (28.8 mL, 320 mmol) was added under nitrogen to asolution of triethylamine (86.6 mL) in dry N,N-dimethylformamide (220mL) at 80° C. Stirred at 100° C. for 15 mins. A solution of2,3-difluoro-6-methoxybenzaldehyde (55.1 g, 320 mmol) inN,N-dimethylformamide (80 mL) was added and the mixture heated at 130°C. for 3 h. Allowed to cool then poured onto ice-water (2 L). Theresulting yellow solid was filtered, washing with water (2×200 mL).Dried under vacuum over phosphorus pentoxide at room temperatureovernight to give the title compound (67.2 g, 87%); δ_(H) (300 MHz,CDCl₃) 8.20 (1H, d, ArH), 7.06 (1H, t, ArH), 6.68 (1H, m, ArH) and 3.99(6H, s, OCH₃ and CO₂CH₃).

c) 7-Fluoro-4-methoxy-1-benzothiophene-2-carboxylic acid

A mixture of methyl 7-fluoro-4-methoxy-1-benzothiophene-2-carboxylate(67.2 g, 280 mmol), sodium hydroxide (45 g, 1.12 mol), methanol (800 mL)and water (400 mL) were stirred at ambient overnight. The methanol wasevaporated and the mixture cooled to 0° C. Acidified with concentratedhydrochloric acid and stirred for 20 mins. The yellow solid wasfiltered, washing with water (3×100 mL). Dried under vacuum at 45° C.overnight, over phosphorus pentoxide to give the title compound (61.4 g,97%); δ_(H) (300 MHz, d₆-DMSO) 8.10 (1H, d, ArH) 7.44 (1H, t, ArH) 7.00(1H, m, ArH) and 4.02 (3H, s, OCH₃).

d) 7-Fluoro-4-methoxy-1-benzothiophene

A mixture of 7-fluoro-4-methoxy-1-benzothiophene-2-carboxylic acid (61.4g, 271 mmol) and copper powder (22.4 g, 352 mmol) in quinoline (500 mL)was heated at 190° C. for 1 h. Cooled to ambient and poured onto aqueoushydrochloric acid (2 N, 750 mL). Stirred with ethyl acetate (500 mL) for15 minutes. Filtered through Celite, washing with ethyl acetate. Theaqueous layer was extracted into ethyl acetate and the combined organiclayers were washed with aqueous hydrochloric acid (2 N, 500 mL), water(500 mL), brine (500 mL), dried over MgSO₄ and evaporated in vacuo.Purified by column chromatography, eluting silica gel withiso-hexane/diethyl ether 0–5% to give the product as a brown oil whichcrystallised to give the title compound (41.3 g, 84%); δ_(H) (300 MHz,CDCl₃) 7.51 (1H, m, ArH), 7.38 (1H, d, ArH), 6.98 (1H, t, ArH), 6.65(1H, dd, ArH) and 3.92 (3H, s, OCH₃).

3-Chloro-4-fluoro-7-methoxy-1-benzothiophene

a) (2E)-3-(2-Fluoro-5-methoxyphenyl)-2-propenoic acid

A solution of 2-fluoro-5-methoxybenzaldehyde (10.00 g, 64.9 mmol),malonic acid (13.4 g, 128.8 mmol), piperidine (2.00 mL) and pyridine(100 mL) was heated to 110° C. for 2 h. After this time the solvent wasremoved in vacuo and the residue taken up in ethyl acetate and washedwith aqueous hydrochloric acid (2N, 100 mL). The organic solvent wasdried (MgSO₄) and the solvent evaporated in vacuo. The solid wasrecrystallised from hot etahanol to give a white solid (12.2 g, 95%);δ_(H) (300 MHz, DMSO) 7.60 (1H, d, J 7 Hz, CH═C), 7.31–7.28 (1H, m, Ar),7.20 (1H, t, Ar), 7.07–6.97 (1H, m, Ar), 6.62 (1H, d, J 8 Hz, CH═CH),3.80 (3H, s, OCH₃).

b) Methyl 3-chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylate

Thionyl chloride (3.7 mL, 50.8 mL) was added to a stirred solution of(2E)-3-(2-fluoro-5-methoxyphenyl)-2-propenoic acid (2.5 g, 12.7 mmol)and pyridine (100 μl). The resulting yellow suspension was stirred at120° C. for 2 h before being allowed to cool to room temperature. Themixture was diluted with dichloromethane (50 mL) and concentrated invacuo. The resulting yellow solid was taken up in methanol (100 mL) andheated to 70° C. for 1 hr. After this time the solvent was removed invacuo to leave a white solid (984 mg, 28%); δ_(H) (300 MHz, CDCl₃)7.09–6.98 (1H, m, Ar), 6.80–6.71 (1H, dd, Ar), 3.98 (6H, s, OCH₃ andCO₂CH₃).

c) 3-Chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid.

Methyl 3-chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylate (2.00g, 7.29 mmol) was suspended in THF:H₂O [10:1] and lithium hydroxide (260mg) added, the resulting suspension was heated to 40° C. for 1 h. Aftercooling to room temperature the mixture was extracted with diethyl ether(50 mL) and the aqueous phase acidified to pH 2 and the solid collectedby filtration and vacuum dried to give a white solid (1.09 g, 58%);δ_(H) (300 MHz, DMSO) 7.32–7.20 (1H, m, Ar), 7.15–7.05 (1H, dd, Ar),3.98 (3H, s, OCH₃).

d) 3-Chloro-4-fluoro-7-methoxy-1-benzothiophene.

A mixture of 3-chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylicacid (1.09 g, 4.19 mmol) and diazobicycloundecane (DBU) (2 mL) indimethylacetamide (15 mL) was heated in a sealed vessel in a microwave(300 W, 100%) for 1 h. After cooling to room temperature the mixture wasdiluted with diethyl ether (100 mL) and washed with brine (2×100 mL).The organic phase was dried (MgSO₄) and the solvent removed in vacuo.The residue was purified by flash chromatography eluting silica gel withhexane:diethyl ether [10:1] to yield a white solid (520 mg, 57%); δ_(H)(300 MHz, CDCl₃) 7.24 (1H, s, Ar), 7.05–6.92 (1H, m, Ar), 6.70–6.60 (1H,dd, Ar), 3.96 (3H, s, OCH₃).

4-Fluoro-7-methoxy-3-methyl-1-benzothiophene

1-[(5-fluoro-2-methoxyphenyl)thio]acetone (1.00 g, 4.67 mmol) was addedto a stirred solution of polyphosphoric acid (2.00 g) and chlorobenzene(70 mL). The resulting solution was stirred rapidly at 160° C. for 18 h.After this time the solution was allowed to cool to room temperature andwashed with water (50 mL). The aqueous phase was extracted withdichloromethane (3×30 mL) and the combined organic extracts dried(MgSO₄). The solvent was removed in vacuo and the residue purified byflash chromatography eluting silica gel with hexane:ethyl acetate [10:1]to give a pale yellow oil (700 mg, 76%); R_(f)=0.72 in hexane:ether[10:1]; δ_(H) (300 MHz, CDCl₃) 7.44–7.20 (1H, m, Ar), 6.99–6.82 (1H, m,Ar), 6.62–6.55 (1H, dd, Ar), 3.95 (3H, s, OCH₃), 2.56 (3H, s, CH₃).

Similarly prepared was

7-Fluoro-4-methoxy-3-methyl-benzothiophene as an oil (1.43 g, 91%);δ_(H) (300 MHz, CDCl₃) 7.22 (1H, s, ArH), 6.89–6.81 (1H, m, ArH),6.59–6.52 (1H, m, ArH), 3.81 (3H, s, OCH₃) and 2.56 (3H, s, CH₃).

2-Fluoro-7-methoxy-1-benzothiophene

A solution of 1-benzothien-7-yl methyl ether (230 mg, 1.40 mmol) in dryTHF (5 mL) was added dropwise to a freshly prepared solution of 2,2,6,6tetramethyl-lithio-piperidine (1.68 mmol) in THF (10 mL) at −78° C. Theresulting solution was stirred at this temperature for 30 mins beforeperchloryl fluoride gas was condensed into the reaction. After thestrong exotherm had stopped the mixture was allowed to stir at −78° C.for a further 30 mins. After this time the reaction was quenched withNH₄Cl (sat, 20 mL) and diluted with diethyl ether. The organic phase wasdried (MgSO₄) and the solvent removed in vacuo. The residue was purifiedby flash chromatography eluting silica gel with hexane to yield acolourless oil (128 mg, 50%); δ_(H) (300 MHz, CDCl₃) 7.32–7.20 (2H, m,Ar), 6.80–6.62 (2H, m, Ar), 3.95 (3H, s, OCH₃).

Similarly prepared was

2-Fluoro-4-methoxy-1-benzothiophene as a colourless oil (420 mg, 48%);δ_(H) (300 MHz, CDCl₃) 7.32–7.20 (2H, m, Ar), 6.80–6.62 (2H, m, Ar),3.95 (3H, s, OCH₃).

7-Methoxy-1-benzothiophene-2-carbonitrile

To a solution of 1-benzothien-7-yl methyl ether (1 g, 6.1 mmol) in THF(12 mL) at −78° C. was added a solution of 2.5 M n-butyllithium inhexanes (2.9 mL, 7.3 mmol). After stirring for 1.5 hr this solution wasadded dropwise to a solution of tosyl cyanide (1.66 g, 9.1 mmol) in THF(8 mL), this was left stirring at −78° C. for 0.5 hr and then warmed toroom temperature. After 16 h this was poured onto ice-water andextracted with dichloromethane (3×50 mL). The combined organic extractswere washed with water, dried (MgSO₄) and the solvent removed in vacuoto give an oil. This was purified by flash chromatography with agradient of 0–30% ethyl acetate in hexane to give the title compound(0.31 g, 27%); δ_(H) (300 MHz, CDCl₃) 7.79 (1H, s, 3-ArH), 7.46–7.38(1H, m, 4-ArH), 7.37–7.31 (1H, m, 5-ArH), 6.88–6.82 (1H, m, 6-ArH) and3.94 (3H, s, OCH₃). Starting material 1-benzothien-7-yl methyl ether wasrecovered from the reaction (0.56 g, 56%); δ_(H) (300 MHz, CDCl₃)7.45–7.29 (4H, m, ArH), 6.75 (1H, m, ArH), 4.00 (3H, s, OCH₃).

7-Methoxy-1-benzothiophene-2-carbonitrile

a) 2-Iodo-7-methoxy-1-benzothiophene

In a 4 L mechanically stirred reactor, a solution of 1-benzothien-7-ylmethyl ether (105 g, 0.64 mol) in anhydrous THF (2 L) is cooled down to−74° C. n-Butyl lithium in hexane is added (2.5 N, 285 mL, 0.71 mol)within 45 min, keeping temperature below −70° C. The mixture is stirred30 min at −78° C. and a solution of iodine (179 g, 0.70 mol) inanhydrous THF (1 L) is added within 1 h, keeping temperature below −70°C. After addition, the mixture is allowed to come up to room temperatureover 2 h and brine (500 mL) is added. The layers are roughly separatedand the organic layer is partially evaporated. Additional brine (200 mL)is added to the residual aqueous layer (mixed with some THF). Afterdecantation, the organic and aqueous layers are separated. The aqueouslayer is extracted with ethyl acetate (500 mL). The organic layers arepooled, washed with aqueous sodium thiosulphate, dried (MgSO₄) and thesolvent evaporated in vacuo to give the crude iodo derivative (173.6 g,93%) The solid is recrystallized from isopropanol (150 mL) to give purecompound (145.5 g, 88%); δ_(H) (600 MHz, CDCl₃) 7.51 (s, 1H), 7.32(d(br), J=7.89 Hz, 1H), 7.26 (t, J=7.89 Hz, 1H), 6.72 (d(br), J=7.89 Hz,1H), 3.97 (s, 3H).

b) 7-Methoxy-1-benzothiophene-2-carbonitrile

A solution of 2-iodo-7-methoxy-1-benzothiophene (10.0 g, 0.35 mol),copper (1) cyanide (6.17 g, 0.68 mol) and anhydrousN,N-dimethylformamide (40 mL) are warmed to 130° C. After 2.5 h at 130°C. no starting material is detectable as measured by HPLC at 220 nm. Thereaction is cooled to 40° C. and a solution 25% v/v ethylenediamine inwater (30 mL) and toluene (20 mL) are added. The mixture is stirred toroom temperature. Additional toluene (30 mL) is added and theheterogeneous mixture is filtered. The layers of the mother liquors areseparated and the aqueous layer is extracted with toluene (3×50 mL). Thecombined organic extracts were washed with water (2×50 mL), dried(MgSO₄) and the solvent evaporated in vacuo to give the title compound(5.78 g, 88%), which was used without further purification; δ_(H) (300MHz, CDCl₃) 7.79 (1H, s, 3-ArH), 7.46–7.38 (1H, m, 4-ArH), 7.37–7.31(1H, m, 5-ArH), 6.88–6.82 (1H, m, 6-ArH) and 3.94 (3H, s, OCH₃).

4-Methoxy-1-benzothiophene-2-carbonitrile

(Ref: Cheutin et al.; C. R. Hebd. Seances Acad. Sci; 261; 1965; 705.) Asolution of 4-methoxy-1-benzothiophene-2-carboxylic acid (1.19 g, 5.7mmol) in pyidine (25 mL) at 0° C. was treated with methanesulfonylchloride (0.49 mL, 6.3 mmol) keeping the temperature at 0° C., stirringwas continued for 2 h. Ammonia gas was then bubbled through the mixturefor 5 minutes, followed by nitrogen for 10 mins. The reaction mixturewas then treated with a large excess of mesyl chloride (4.43 mL, 57mmol) and stirred for 16 h at room temperature. The solvent evaporatedin vacuo to give a brown residue which was purified by flashchromatography with 10% ethyl acetate in hexane to give a colourlesssolid (800 mg, 74%); δ_(H) (300 MHz, CDCl₃) 8.00 (1H, s, 3-ArH),7.48–7.35 (2H, m, ArH), 6.80–6.77 (1H, m, ArH) and 3.92 (3H, s, OCH₃).

4-Fluoro-7-methoxy-1-benzothiophene-2-carbonitrile

a) 4-Fluoro-7-methoxy-1-benzothiophene-2-carboxamide

A solution of 4-fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (1.5g, 6.6 mmol) in thionyl chloride (4 mL) was heated to 50° C. for 30minutes, then the solvent removed in vacuo. The residue was taken up indichloromethane (60 mL) and methanol (0.5 mL) and then added to asolution of concentrated ammonium hydroxide (40 mL) and dichloromethane(40 mL) at 5° C. After 10 min the solution was warmed to roomtemperature and stirred for 2 h. The dichloromethane was evaporated invacuo and the solid filtered to give a pale browm solid (0.75 g, 51%);δ_(H) (300 MHz, D₄-Methanol) 7.95 (1H, s, 3-ArH), 7.02–6.92 (1H, m,ArH), 6.83–6.77 (1H, m, ArH), 3.89 (3H, s, OCH₃) and 3.23–3.28 (2H, m,CONH₂).

b) 4-Fluoro-7-methoxy-1-benzothiophene-2-carbonitrile

A solution of 4-fluoro-7-methoxy-1-benzothiophene-2-carboxamide (0.756g, 3.3 mmol) in phosphorus oxychloride (6.2 mL, 6.6 mmol) was refluxedfor 3 h then cooled and the solvent evaporated in vacuo to give thetitle compound. Purified by flash chromatography with a gradient of0–30% ethyl acetate in iso-hexane to give a colourless solid (0.635 g,91%); δ_(H) (300 MHz, CDCl₃) 7.95 (1H, s, 3-ArH), 7.10–7.01 (1H, m,ArH), 6.85–6.77 (1H, m, ArH) and 3.98 (3H, s, OCH₃).

4-Cyano-7-methoxy benzo[b]thiophene.

To a stirred solution of 4-bromo-7-methoxy benzo[b]thiophene (1.05 g,4.32 mmol, 1 equiv.) in dry DMF (40 mL) was added copper(I)cyanide(3.885 g, 43.4 mmol, 10 equiv.) and the reaction mixture was heated at150° C. overnight. The reaction mixture was cooled to ˜120° C. and thensolid iron(III)chloride (1.58 g, 9.74 mmol) was added followed by 1 NHCl (CAUTION: HCN evolution—perform in a well vented hood!) The reactionmixture was heated at ˜100° C. for 2 hr before cooling to roomtemperature. Water, brine, and ethyl acetate were added and the layerswere separated. The organic layer was washed with brine (3 times), driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The crude residue thus obtained was purified viamedium pressure liquid chromatography eluting with 10% ethyl acetate/90%hexanes to afford the title compound (564 mg, 69%) as a colorless solid;□_(H) (400 MHz, CDCl₃) 4.06 (3H, s), 6.81 (1H, d, J=8 Hz), 7.56 (1H, d,J=6 Hz), 7.65 (1H, d, J=6 Hz), 7.71 (1H, d, J=8 Hz).

Ref: (J. Chem. Soc. Perkin Trans 1 1983, 2973).

6-Methoxy-1-benzothiophene-2-carbonitrile

a) O-(2-Formyl-5-methoxyphenyl) dimethylthiocarbamate

A solution of N,N-dimethylcarbamoyl chloride (4.46 g, 35.7 mmol) in THF(20 mL) was added over 15 minutes to a stirred cooled (0° C.), solutionof 2-hydroxy-4-methoxybenzaldehyde (5 g, 32.9 mmol) and potassiumhydroxide (2 g, 35.7 mmol) in water (25 mL) such that the temperaturedid not rise above 10° C. The mixture was stirred for 10 minutes at roomtemperature then extracted with ethyl acetate (3×50 mL), the combinedorganic layers were washed successively with 2M sodium hydroxide (100mL), 2N hydrochloric acid (100 mL), brine (100 mL) then dried (MgSO₄)and the solvent removed in vacuo to give a yellow solid (6.8 g, 86%)which was used without further purification; δ_(H) (300 MHz, CDCl₃)7.88–7.80 (1H, m, ArH), 7.95–7.85 (1H, m, ArH), 6.65–6.60 (1H, m, ArH),3.88 (3H, s, OCH₃), 3.46 (3H, s, N(CH₃)₂) and 3.40 (3H, s, N(CH₃)₂).

b) S-(2-Formyl-5-methoxyphenyl) dimethylthiocarbamate

A pre-warmed solution of O-(2-formyl-5-methoxyphenyl)dimethylthiocarbamate (2 g, 8.3 mmol) in diphenyl ether (4 mL) was addedto diphenyl ether (36 mL) at 230° C. The mixture was heated at 230° C.for 1.5 h. The reaction mixture was loaded neat onto flashchromatography column and solvent eluted with iso-hexane. Product elutedwith a gradient of 0–30% ethyl acetate in iso-hexane. Further purifiedby flash chromatography with a gradient of 0–20% ethyl acetate indichloromethane, followed by triturating with iso-hexane gave a solidwhich was recrystallised from ethyl acetate hexane to give the titlecompound (1.21 g, 61%); δ_(H) (300 MHz, CDCl₃) 8.04–7.95 (1H, m, ArH),7.09–6.99 (2H, m, ArH), 3.89 (3H, s, OCH₃), 3.16 (3H, br. s, N(CH₃)₂)and 3.02 (3H, br, s, N(CH₃)₂).

c) 6-Methoxy-1-benzothiophene-2-carbonitrile

(Ref: Gallagher, T; Pardoe, D. A.; Porter, R.; Tetrahedron Lett.; 2000,41(28), 5415–5418.) To a solution of S-(2-formyl-5-methoxyphenyl)dimethylthiocarbamate (1.08 g, 4.5 mmol) in water (4 mL) and methanol (8mL) was added sodium hydroxide (199 mg, 4.9 mmol), this was heated toreflux for 16 hours. The reaction was cooled to room temperature andchloroacetonitrile (0.28 mL, 4.5 mmol) was added in one portion and themixture the stirred at room temperature for 1 hour. The methanol wasremoved in vacuo, and water (10 mL) added. The aqueous layer wasextracted with diethyl ether (3×20 mL), dried (MgSO₄) and the solventremoved in vacuo. The residue was purified by flash chromatography witha gradient of 0–30% ethyl acetate in iso-hexane to give the titlecompound as a colourless solid (390 mg, 46%); δ_(H) (300 MHz, CDCl₃)7.80–7.70 (1H, m, ArH), 7.29 (2H, m, ArH), 7.11–7.01 (1H, m, ArH) and3.85 (3H, s, OCH₃). M+23=212.0. ν_(max)/cm⁻¹ [film] 2213.50 (m).

1-Benzothiophen-4-ol

a) 5-Bromo-6,7-dihydro-1-benothiophen-4(5H)-one

Ref: J. Chem. Res. (S) 1993, 192–193. Bromine (6.4 g, 40 mmol) in drycarbon tetrachloride containing a few drops of diethyl ether (20 mL) wasadded dropwise to a well stirred solution6,7-dihydro-1-benothiophen-4(5H)-one (6.08 g; 40 mmol) in dry diethylether (250 mL) allowing the solution to decolourise between additionsand the temperature maintained at −10° C. Once the addition wascomplete, the solution was allowed to warm slowly to room temperature.Water (200 mL) was slowly added and the mixture transferred to aseparating funnel with ether (100 mL). The organic phase was washed withwater (100 mL), dried over magnesium sulfate and evaporated to an oilwhich solidified on standing (8.56 g, 88%), this material was usedwithout further purifictaion. δ_(H) (300 MHz, CD₃OD) 7.36 (1H, d, Ar)7.30 (1H, d, Ar), 4.63 (1H, t, CH) 3.20 (2H, m, CH₂), 2.56 (2H, m, CH₂).

b) 1-Benzothiophen-4-ol

5-Bromo-6,7-dihydro-1-benothiophen-4(5H)-one (11.4 g, 50 mmol), lithiumbromide (10 g) and lithium carbonate (7.4 g) were refluxed for 3 h indry N,N-dimethylformamide (250 mL) under nitrogen. The solvent wasevaporated in vacuo and the residue treated with cold aqueoushydrochloric acid (1 N, 250 mL). Extracted into diethyl ether (3×200mL). The ethereal layer was extracted with 10% aqueous sodium hydroxidesolution (2×). Combined aqueous layers were acidified and extracted intoether. Dried over magnesium sulfate and evaporated to an oil. Purifiedby chromatography eluting silica gel with ethyl acetate—hexane (4–6%).Combined fractions were evaporated to a light yellow oil whichcrystallised on standing, this material was triturated with cyclohexaneto give white plates (3.6 g; 51%). δ_(H) (300 MHz, CD₃OD) 7.45 (1H, d,Ar), 7.30–7.40 (2H, m, Ar), 7.12 (1H, m, Ar), 6.70 (1H, m, Ar).

Boron Tribromide Demethylation: General Procedure

1-Benzothiophen-7-ol

A solution of boron tribromide (115 μl, 1.21 mmol) was added dropwise atroom temperature to a stirred solution of 1-benzothiophen-7-ol (200 mg,1.21 mmol) in dry dichloromethane (10 mL). The resulting solution wasallowed to stir at room temperature for a further 1 hr, after which thesolvent was removed in vacuo and the residue taken up in ethyl acetate(20 mL) and extracted with aqueous hydrochloric acid (2 N, 10 mL). Theorganic phase was dried (MgSO₄) and the solvent was removed in vacuo.The resulting dark yellow oil was purified by flash chromatographyeluting silica gel with hexane:ethyl acetate [4:1] to yield a whitesolid (68 mg, 38%); δ_(H) (300 MHz, CDCl₃) 7.50–7.39 (2H, m, Ar),7.29–7.21 (1H, m, Ar), 7.21–7.15 (1H, m, Ar), 6.70 (1H, d, Ar), 5.15(1H, bs, OH).

Similarly prepared were

5-Fluoro-1-benzothiopbene-7-ol as a brown crystalline solid (393 mg,42%); δ_(H) (300 MHz, CDCl₃) 7.50 (1H, d, Ar), 7.28 (1H, d, Ar), 7.10(1H, dd, Ar), 6.58 (1H, dd, Ar), 5.40 (1H, s, OH).

4-Trifluoromethyl-1-benzothiophen-6-ol as a brown crystalline solid(1.576 g, 62%); δ_(H) (300 MHz, CDCl₃) 7.50–7.40 (3H, m, Ar), 7.22 (1H,d, Ar), 5.30 (1H, bs, OH).

5-Fluoro-1-benzothiophen-4-ol as a white crystalline solid (0.074 g,21%); δ_(H) (300 MHz, CDCl₃) 7.50 (1H, d, Ar), 7.42 (1H, d, Ar), 7.35(1H, m, Ar), 7.10 (1H, t, Ar), 5.40 (1H, bs, OH).

4-Methyl-1-benzothiophen-7-ol as an oil (290 mg, 79%); δ_(H) (300 MHz,CDCl₃) 7.44 (1H, d, Ar), 7.32 (1H, d, Ar), 7.00 (1H, d, Ar), 6.61 (1H,d, Ar), 4.92 (1H, s, OH), 2.52 (3H, s, CH₃).

7-Fluoro-1-benzothiophen-4-ol as a solid (0.68 g, 79%); δ_(H) 7.45 (1H,m, ArH), 7.40 (1H, d, ArH), 6.90 (1H, t, ArH) and 6.74 (1H, m, ArH) and5.00 (1H, br. s, OH).

3-Chloro-4-fluoro-1-benzothiophen-7-ol as a white solid (145 mg, 97%);δ_(H) (300 MHz, CDCl₃) 7.25 (1H, s, Ar), 7.05–6.85 (1H, m, Ar),6.72–6.61 (1H, dd, Ar).

3-Methyl-4-fluoro-1-benzothiophen-7-ol as a white solid (447 mg, 69%);δ_(H) (300 MHz, CDCl₃) 7.28 (1H, s, Ar), 6.99 (1H, s, OR), 6.90–6.78(1H, m, Ar), 6.60 (1H, dd, Ar), 2.57 (3H, s, CH₃).

7-Fluoro-3-methyl-1-benzothiophen-4-ol as a solid (0.77 g, 70%); δ_(H)(300 MHz, CDCl₃) 7.26 (1H, s, ArH), 6.85–6.77 (1H, m, ArH), 6.58–6.50(1H, m, ArH), 4.98 (1H, s, OH) and 2.65 (3H, s, CH₃).

2-Fluoro-1-benzothiophen-7-ol as a colourless oil (502 mg, 50%); δ_(H)(300 MHz, CDCl₃) 7.35–7.12 (3H, m, Ar), 6.72–6.63 (1H, dd, Ar).

2-Fluoro-1-benzothiophen-4-ol as a colourless oil (213 mg, 55%); δ_(H)(300 MHz, CDCl₃) 7.44 (1H, d, Ar), 7.41–7.12 (2H, m, Ar), 6.72–6.63 (1H,dd, Ar).

7-Hydroxy-1-benzothiophene-2-carbonitrile as a solid (3.9 g, 74%). δ_(H)(250 MHz, DMSO-D6) 6.98 (dd, J=7.87, 0.94 Hz, 1H) 7.37 (t, J=7.87 Hz,1H) 7.49 (dd, J=7.87, 0.94 Hz, 1H) 8.34 (s, 1H) 10.87 (s, 1H). NegativeFIA: M−1=174.1.

4-Hydroxy-1-benzothiophene-2-carbonitrile as a solid (0.65 g, 95%) δ_(H)(300 MHz, CDCl₃) 8.05 (1H, s, 3-ArH), 7.43–7.34 (2H, m, ArH), 7.80–7.75(1H, m, ArH) and 5.68 (1H, br. s, OH). Negative FIA: M−1=174.1.

4-Fluoro-7-hydroxy-1-benzothiophene-2-carbonitrile as a solid (160 mg,27%); δ_(H) (300 MHz, CDCl₃) 7.94 (1H, s, 3-ArH), 7.04–6.92 (1H, m,ArH), 6.85–6.76 (1H, m, ArH) and 5.52 (1H, br. s, OH).

6-Hydroxy-1-benzothiophene-2-carbonitrile as a solid; (0.36 g, 64%);δ_(H) (300 MHz, D₄-Methanol) 7.85 (1H, s, ArH), 7.73–7.62 (1H, m, ArH),7.16 (1H, s, ArH) and 6.95–6.83 (1H, m, ArH). M+1=176.1.

1-Benzofuran-7-ol, synthesised from 7-methoxy-1-benzofuran, (Ref:Musser, J. H.; Chakraborty, U; Bailey, K; Sciortino, S; Whyzmuzis, C;Amin, D; Sutherland, C. A. J. Med. Chem. (1987), 30(1), 62–7.) as asolid (0.73 g, 82%); δ_(H) (300 MHz, CDCl₃) 7.61 (1H, d, Ar), 7.16 (2H,m, Ar), 6.82 (2H, m, Ar), 5.37 (1H, bs, —OH).

6-Fluoro-1-benzothiophene-7-ol

(Ref: Briner, K; Burkholder, T. P; Conway, R. G; Cunningham, B. E;Finley, D. R; Heinz, L. J; Jesudason, C. D; Kohlman, D. T; Liang, S. X;Xu, Y. C. Preparation and use of serotonergic benzothiophenes. WO0109126 A1. Chem. Abs. 134:162912). To a solution of7-bromo-6-fluoro-1-benzothiophene (0.2 g, 0.9 mmol) and trimethylborate(0.2 mL, 1.8 mmol) at −78° C. was added tert-butyllithium dropwise.After 10 mins at −78° C. the reaction was quenched by pouring ontosaturated ammonium chloride. This was extracted with ethyl acetate (3×10mL) and the solvent removed in vacuo from the combined organic extracts.The residue was taken up in ethyl acetate (4 mL) and 10% aqueoushydrochloric acid (4 mL) was added, the mixture was stirred at roomtemperature for 1 h. The organic layer was separated and the aqueouslayer extracted with ethyl acetate (2×10 mL). The combined organicextracts were dried (MgSO₄) and the solvent removed in vacuo. Theresidue was taken up in THF (10 mL), water (2 mL) and cooled to 0° C.then 10% aqueous sodium hydroxide (2 mL) and 28% hydrogen peroxide (1mL) were added to this and stirred for 0.5 h at 0° C. The mixture waswarmed to room temperature and stirred for 2 hours, before a acetic acid(3 mL) was added. The mixture was extracted with ethyl acetate (3×10mL), dried (MgSO₄) and the solvent removed in vacuo, to give a purplesolid. This was purified by flash chromatography with a gradient of0–20% ethyl acetate in iso-hexane to give the title compound (56 mg,38%); δ_(H) (300 MHz, CDCl₃) 7.41 (4H, m, ArH).

4-Cyano-7-hydroxy benzo[b]thiophene

To a solution of 4-cyano-7-methoxy benzo[b]thiophene (450 mg, 2.38 mmol,1 equiv.) in dry DMF (20 mL) was added sodium ethanethiolate (80%technical grade, 1.34 g, ˜13 mmol, ˜5 equiv.) and the reaction mixturewas heated at 150° C. for 2 hr. The mixture was cooled to roomtemperature and ethyl acetate and 1N HCl were added and the layers wereseparated. The aqueous layer was extracted with ethyl acetate and thecombined organic extracts were washed with brine (3 times), dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The acquired material thus obtained was purified via mediumpressure liquid chromatography eluting with 30% ethyl acetate/70%hexanes to afford the title compound (414 mg, 99%) as a colorless solid;□_(H) (400 MHz, CD₃OD) 6.80 (1H, d, J=8 Hz), 7.47 (1H, d, J=6 Hz), 7.64(1H, d, J=8 Hz), 7.83 (1H, d, J=6 Hz).

1-Methyl-1H-indol-5-ol

(Ref: Taborsky, R. G.; Delvigs, P; Palaic, D; Bumpus, F. M. J. Med.Chem. (1967), 10(3), 403–7). To a solution of5-benzyloxy-1-methyl-1H-indole (2 g, 8.9 mmol) in ethanol (20 mL) wasadded potassium hydroxide (0.62 g, 11.2 mmol). The resulting solutionwas allowed to stir at room temperature for 10 mins before evaporatingthe ethanol in vacuo. The residue was taken up in acetone (75 mL) andsodium sulfate (6.4 g, 44.8 mmol) was added, followed by dimethylsulfate (0.87 mL, 8.9 mmol) via syringe. The solution was stirred for0.5 h, then filtered and evaporated in vacuo. The resulting residue wasthen taken up in ethanol (50 mL) and 10% palladium on charcoal (0.4 g)was added. This solution was stirred under a hydrogen atmosphere for 4h, then filtered through celite and the solvent evaporated in vacuo.This material was purified by flash chromatography, eluting silica gelwith hexane:ethyl acetate (100:0 to 50:50) to give the product. (0.48 g,37%); δ_(H) (300 MHz, CDCl₃) 7.15 (1H, d, Ar), 7.01 (2H, m, Ar), 6.8(1H, m, Ar), 6.32 (1H, m, Ar), 3.73 (3H, s, NCH₃).

1-Methyl-1H-indol-7-ol

a) 7-Benzyloxy-1-methyl-1H-indole

To a solution of 7-benzyloxy-1H-indole (Ref: Dobson, D; Todd, A;Gilmore, J. Synth. Commun. (1991), 21(5), 611–17) (1.29 g, 5.78 mmol) inethanol (30 mL) was added potassium hydroxide (0.41 g, 7.23 mmol) anddichloromethane (5 mL) of to help solubilize the starting material. Theresulting solution was allowed to stir at room temperature for 10 minbefore evaporating the solvent in vacuo. The residue was taken up inacetone (75 mL) and sodium sulfate (4.9 g, 34.7 mmol) was added followedby dimethyl sulfate via syringe (0.62 mL, 6.3 mmol). The solution wasstirred for 1 h, then filtered and evaporated in vacuo. This materialwas purified by flash chromatography, eluting silica gel withhexane:ethyl acetate (100:0 to 10:1) to give the product. (1.12 g, 82%);Mass spectrum (ion spray): m/z=238.1 (M+1).

b) 1-Methyl-1H-indol-7-ol

To a solution of 7-benzyloxy-1methyl-1H-indole in 20 mL of ethanol wasadded 10% palladium on charcoal (0.2 g). This solution was stirred underballoon pressure hydrogen atmosphere for 4 h, then filtered throughcelite and concentrated in vacuo. This material was purified by flashchromatography, eluting silica gel with hexane:ethyl acetate (100:0 to50:50) to give the product (0.58 g, 87%); Mass spectrum (TOF): m/z=147.1(M).

(1R)-3-Chloro-1-(2-thienyl)-1-pronanol

a) 3-Chloro-1-(2-thienyl)-1-propanone

Chloropropionyl chloride (12 mL, 130 mmol) in dry dichloromethane (50mL) was added dropwise at −5° C. to a stirred suspension of aluminiumchloride (18.8 g, 141 mmol) in dry dichloromethane (100 mL). Theresulting suspension was allowed to stir at −5° C. for 10 mins before asolution of thiophene (10 g, 118 mmol) in dry dichloromethane (50 mL)was added dropwise. The resulting orange solution was stirred at −5° C.for 1 hr before being carefully dropped onto crushed ice (200 g). Theorganic phase was separated and dried (MgSO₄), the solvent was thenpassed through a pad of celite/charcoal to remove any colour. Removal ofthe solvent in vacuo resulted in the title compound as a colourless oil(20 g, 100%); δ_(H) (300 MHz, CDCl₃) 7.75 (1H, d, Ar), 7.68 (1H, d, Ar),7.15 (1H, m, Ar), 3.90 (2H, t, J=7 Hz, CH₂), 3.38 (2H, t, J=7 Hz, CH₂).

b) (1R)-3-Chloro-1-(2-thienyl)-1-propanol

Borane dimethylsulfide complex (2.75 mL, 28.6 mmol) was added at roomtemperature to a stirred solution of (S)-2-methyl-CBS-oxazaborolidine(2.87 mL, 1M) in dry THF (50 mL). The resulting solution was stirred atroom temperature to 10 mins before a solution of3-chloro-1-(2-thienyl)-1-propanone (2.5 g, 14.3 mmol) in dry THF (100mL) was added dropwise over 1 hr. After complete addition the resultingsolution was stirred at room temperature for a further 1 hr before thesolvent was removed in vacuo. The residue was taken up in ether (200 mL)and washed with NH₄Cl (sat, 100 mL). The organic phase was dried (MgSO₄)and concentrated in vacuo. The residue was purified by flashchromatography eluting silica gel with hexane:ether [7:3] to yield acolourless oil (2.1 g, 84%); Optical purity determined by capillaryelectrophoresis to be 83% ee; δ_(H) (300 MHz, CDCl₃) 7.25 (1H, d, Ar),7.08–6.9 (2H, m, Ar), 5.28–5.20 (1H, m, CHO), 3.80–3.52 (2H, m, CH₂),2.35–2.12 (2H, m, CH₂).

7-[(1S)-3-Chloro-1-phenylpropyl]oxy-1-benzothiophene

4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (327 mg, 0.80 mmol) was added in one portion to a stirredsolution of (R)-(+)-3-chloro-1-phenyl-1-propanol (90 mg, 0.53 mmol) and1-benzothiophen-7-ol (80 mg, 0.53 mmol) in dry THF (5 mL) under an inertatmosphere on nitrogen. The resulting suspension was allowed to stir fora further 18 hrs before the solvent was removed in vacuo. The residuewas triturated with hexane (ca. 15 mL) and the solid filtered, thefiltrate was concentrated in vacuo and the resulting pale yellow oil waspurified by flash chromatography eluting silica gel with hexane:ether[95:5] to yield the title compound as a colourless oil (60 mg, 37%);R_(f)=0.8 in hexane:ether [10:1]; δ_(H) (300 MHz, CDCl₃) 7.66–7.00 (9H,m, Ar); 6.55 (1H, d, Ar), 5.80–5.72 (1H, m, CHO), 3.91–3.60 (2H, m,CH₂), 2.62–2.50 (1H, m, CHH), 2.38–2.22 (1H, m, CHH).

Similarly prepared were

4-[(1S)-3-Chloro-1-phenylpropyl]oxy-1-benzothiophene as a colourless oil(120 mg,

51%); δ_(H) (300 MHz, CDCl₃) 7.59–7.01 (9H, m, Ar); 6.55 (1H, d, Ar),5.60–5.42 (1H, m, CHO), 3.84–3.70 (1H, m, CHH), 3.68–3.52 (1H, m, CHH),2.62–2.48 (1H, m, CHH), 2.35–2.29 (1H, m, CHH).

5-[(1S)-3-Chloro-1-phenylpropyl]oxy-1-benzothiophene (from1-benzothiophen-5-ol Ref: Perez-Silanes, S.; Martinez-Esparza, J.;Oficialdegui, A. M.; Villanueva, H.; Orus, L.; Monge, A; J. HeterocyclicChem. 2001, 38(5) 1025.)

as a colourless oil (480 mg, 80%); δ_(H) (300 MHz, CDCl₃) 7.55 (1H, d,Ar), 7.65–6.81 (9H, m, Ar), 5.37–5.25 (1H, m, CHO), 3.79–3.65 (1H, m,CHH), 3.60–3.50 (1H, m, CHH), 2.48–2.32 (1H, m, CHH), 2.20–2.09 (1H, m,CHH).

6-[(1S)-3-Chloro-1-phenylpropyl]oxy-1-benzothiophene (prepared from1-benzothiophen-6-ol Ref: Hansch, C.; Schmidhalter, B., J. Org. Chem.;1955, 20,

1056) as a colourless oil (363 mg, 66%); δ_(H) (400 MHz, CDCl₃) 7.62(1H, d, J=8.0 Hz, Ar), 7.41–7.17 (8H, m, Ar), 7.0 (1H, dd, J=4, 8 Hz,Ar), 5.43 (1H, dd, J=4, 12 Hz, CHO), 3.88–3.81 (1H, m, CHH), 3.67–3.61(1H, m, CHH), 2.54–2.47 (1H, m, CHH), 2.29–2.22 (1H, m, CHH).7-{[(1S)-3-Chloro-1-phenylpropyl]oxy}-4-fluoro-1-benzothiophene

Procedure identical to above to give a colourless oil (670 mg, 76%);δ_(H) (300 MHz, CDCl₃) 7.88–7.00 (8H, m, Ar); 6.55 (1H, d, Ar),5.80–5.72 (1H, m, CHO), 3.91–3.60 (2H, m, CH₂), 2.62–2.50 (1H, m, CHH),2.38–2.22 (1H, m, CHH).

7-{[(1S)-3-Chloro-1-phenylpropyl]oxy}-4-fluoro-3-methyl-1-benzothiophene

as a colourless oil (240 mg, 60%); δ_(H) (300 MHz, CDCl₃) 7.42–7.20 (6H,m, Ar), 6.80–6.74 (1H, m, Ar), 7.45 (1H, dd, Ar), 5.58–5.48 (1H, m,CHO), 4.91–4.80 (1H, m, CHH), 4.71–4.59 (1H, m, CHH), 2.62–2.48 (4H, m,CHH and CH₃), 2.42–2.28 (1H, m, CHH).7-{[(1S)-3-Chloro-1-phenylpropyl]oxy}-4-fluoro-3-chloro-1-benzothiophene.

as a colourless oil (483 mg, 92%); δ_(H) (300 MHz, CDCl₃) 7.40–7.12 (6H,m, Ar), 6.85–6.70 (1H, m, Ar), 6.58–6.47 (1H, m, Ar), 5.55–5.45 (1H, m,CHO), 3.90–3.78 (1H, m, CHH), 3.69–3.59 (1H, m, CHH), 2.61–2.48 (1H, m,CHH), 2.32–2.19 (1H, m, CHH).7-{[(1S)-3-Chloro-1-phenylpropyl]oxy}-4-methyl-1-benzothiophene

Procedure identical to above to give a colourless oil (670 mg, 76%);δ_(H) (300 MHz, CDCl₃) 7.47–7.20 (7H, m, Ar), 6.89 (1H, d, Ar), 6.49(1H, d, Ar), 5.59–5.50 (1H, m, CHO), 3.95–3.80 (1H, m, CHH), 3.72–3.62(1H, m, CHH), 2.62–2.41 (4H, m, CHH and CH₃), 2.32–2.20 (1H, m, CHH).

7-{[(1S)-3-Chloro-1-phenylpropyl]oxy}-2-fluoro-1-benzothiophene

as a colourless oil (350 mg, 74%); δ_(H) (300 MHz, CDCl₃) 7.45–7.02 (8H,m, Ar), 6.64–6.52 (1H, dd, Ar), 5.63–5.50 (1H, m, CHO), 3.90–3.75 (1H,m, CHH), 3.69–3.55 (1H, m, CHH), 2.62–2.48-(1H, m, CHH), 2.32–2.18 (1H,m, CHH).7-{[(1S)-3-Chloro-1-phenylpropyl]oxy}-2-fluoro-1-benzothiophene

as a colourless oil (128 mg, 61%); δ_(H) (300 MHz, CDCl₃) 7.48–6.50 (9H,m, Ar), 5.58–5.48 (1H, m, CHO), 3.90–3.78 (1H, m, CHH), 3.70–3.58 (1H,m, CHH), 2.61–2.45 (1H, m, CHH), 2.37–2.20 (1H, m, CHH).7-[(1S)-3-Chloro-1-phenylpropyl]oxy-5-fluoro-1-benzothiophene

as a colourless oil (300 mg, 84%); R_(f)=0.5 in hexane:EtOAc [90:10];δ_(H) (300 MHz, CDCl₃) 7.48 (1H, d, Ar), 7.40–7.20 (6H, m, Ar); 7.05(1H, dd, Ar), 6.40 (1H, dd, Ar), 5.52 (1H, m, CHO), 3.91–3.60 (2H, m,CH₂), 2.62–2.20 (2H, m, CH₂).6-[(1S)-3-Chloro-1-phenylpropyl]oxy-4-trifluoromethyl-1-benzothiophene

as a pale yellow oil (216 mg, 76%); R_(f)=0.4 in hexane:EtOAc [90:10];δ_(H) (300 MHz, CDCl₃) 7.40–7.20 (9H, m, Ar); 5.45 (1H, m, CHO),3.90–3.50 (2H, m, CH₂), 2.58–2.20 (2H, m, CH₂).4-[(1S)-3-Chloro-1-phenylpropyl]oxy-5-fluoro-1-benzothiophene

as a colourless oil (36 mg, 47%); R_(f)=0.4 in hexane:ethyl acetate[90:10]; δ_(H) (300 MHz, CDCl₃) 7.40–7.20 (8H, m, Ar); 7.00 (1H, t, Ar),5.58 (1H, m, CHO), 3.90–3.60 (2H, m, CH₂), 2.80–2.22 (2H, m, CH₂).4-{[(1S)-3-Chloro-1-phenyl-propyl]oxy}-7-fluoro-1-benzothiophene

as a solid (0.30 g, 79%); δ_(H) (300 MHz, CDCl₃) 7.52–7.50 (1H, m, ArH),7.35–7.15 (6H, m, ArH), 6.71–6.65 (1H, m, ArH), 6.42–6.39 (1H, m, ArH),5.42–5.36 (1H, m, CHO), 3.80–3.70 (1H, m, CH₂CHHCl), 3.61–3.51 (1H, m,CH₂CHHCl), 2.52–2.41 (1H, m, CHHCH₂Cl) and 2.28–2.13 (1H, m, CHHCH₂Cl).4-{[(1S)-3-Chloro-1-phenyl-propyl]oxy}-7-fluoro-3-methyl-1-benzothiophene

as a solid (0.25 g, 67%); δ_(H) (300 MHz, CDCl₃) 7.42–7.22 (5H, m, ArH),6.97 (1H, s, ArH), 6.70–6.68 (1H, m, ArH), 6.45–6.40 (1H, m, ArH),5.52–5.43 (1H, m, CHO), 3.83–3.75 (1H, m, CH₂CHHCl), 3.63–3.56 (1H, m,CH₂CHHCl), 2.76 (3H, s, OCH₃), 2.60–2.49 (1H, m, CHHCH₂Cl) and 2.34–2.22(1H, m, CHHCH₂Cl).7-{[(1S)-3-Chloro-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

as a solid (0.22 g, 65%); δ_(H) (300 MHz, CDCl₃) 7.95 (1H, s, 3-ArH),7.47–7.20 (7H, m, ArH), 6.79–6.71 (1H, m, ArH), 5.62–5.55 (1H, m, CHO),3.91–3.78 (1H, m, CH₂CHHCl), 3.69–3.58 (1H, m, CH₂CHHCl), 2.68–2.52 (1H,m, CHHCH₂Cl) and 2.49–2.25 (1H, m, CHHCH₂Cl).4-{[(1S)-3-Chloro-1-phenylpropyl]-oxy}-1-benzothiophene-2-carbonitrile

as a solid (0.15 g, 72%); δ_(H) (300 MHz, CDCl₃) 8.07 (1H, s, 3-ArH),7.35–7.17 (7H, m, ArH), 6.61–6.58 (1H, m, ArH), 5.53–5.48 (1H, m, CHO),3.80–3.68 (1H, m, CH₂CHHCl), 3.60–3.49 (1H, m, CH₂CHHCl), 2.60–2.48 (1H,m, CHHCH₂Cl) and 2.28–2.17 (1H, m, CHHCH₂Cl).4-Cyano-7-[(1S)-3-chloro-1phenylpropyl]oxy-1-benzo[b]thiophene

□_(H) (400 MHz, CDCl₃) 7.60 (1H, d, J=6 Hz), 7.48 (1H, d, J=6 Hz), 7.45(1H, d, J=8 Hz), 7.15–7.35 (5H, m), 6.58 (1H, d, J=8 Hz), 5.60 (1H, dd,J=8, 4 Hz), 3.73–3.82 (1H, m), 3.53–3.62 (1H, m), 2.49–2.60 (1H, m),2.20–2.31 (1H, m).5-[(1S)-3-Chloro-1-phenylpropyl]oxy-1-methyl-1H-indole

as a solid (183 mg, 41%); mass spectrum (TOF): m/z=299.11 (M).7-[(1S)-3-Chloro-1-phenylpropyl]oxy-1-indole

as a colourless oil (200 mg, 41%); (1H NMR CDCl3) 8.42 (1H, s, NH),7.42–7.05 (8H, m, Ar), 6.82 (1H, t, Ar), 6.56–6.41 (1H, m, Ar),5.55–5.45 (1H, m, CHO), 3.91–3.80 (1H, m, CHH), 3.72–3.60 (1H, m, CHH),2.60–2.46 (1H, m, CHH), 2.32–2.20 (1H, m, CHH).7-[(1S)-3-Chloro-1-phenylpropyl]oxy-1-indole

as a colourless oil (110 mg, 51%); δ_(H) (300 MHz, CDCl₃) 8.15 (1H, s,NH), 7.45 (2H, d, Ar), 7.32 (2H, t, Ar), 7.30–7.22 (1H, m, Ar), 7.15(1H, t, Ar), 7.00–6.92 (2H, m, Ar), 6.72 (1H, t, Ar), 6.35 (1H, d, Ar),5.58–5.50 (1H, m, CHO), 3.92–3.82 (1H, m, CHH), 3.72–3.62 (1H, m, CHH),2.65–2.52 (1H, m, CHH), 2.35–2.25 (1H, m, CHH).4-{[(1S)-3-Iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

To a solution7-{[(1S)-3-chloro-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile(218 mg, 0.6 mmol) in acetone (8 mL) was added sodium iodide (1.01 g, 6mmol). This was heated to reflux for 48 h and cooled to roomtemperature, water (20 mL) was added and the aqueous layer extractedwith diethyl ether (3×20 mL). The combined organic layers were washedwith brine, dried (MgSO₄) and the solvent removed in vacuo to give asolid (0.22 g, 80%); δ_(H) (300 MHz, CDCl₃) 7.85 (1H, s, 3-ArH),7.43–7.19 (7H, m, ArH), 6.81–6.78 (1H, m, ArH), 5.52–5.42 (1H, m, CHO),3.51–3.34 (1H, m, CH₂CHHI), 3.32–3.20 (1H, m, CH₂CHHI), 2.67–2.53 (1H,m, CHHCH₂I) and 2.42–2.30 (1H, m, CHHCH₂I).

Similarly prepared was

7-{[(1S)-3-Iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

as a solid (0.22 g, 80%); δ_(H) (300 MHz, CDCl₃) 7.85 (1H, s, 3-ArH),7.43–7.19 (7H, m, ArH), 6.81–6.78 (1H, m, ArH), 5.52–5.42 (1H, m, CHO),3.51–3.34 (1H, m, CH₂CHHI), 3.32–3.20 (1H, m, CH₂CHHI), 2.67–2.53 (1H,m, CHHCH₂I) and 2.42–2.30 (1H, m, CHHCH₂I).4-Fluoro-7-{[(1S)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (383 mg, 0.93 mmol) was added in one portion to a stirredsolution of (R)-3-iodo-1-phenyl-1-propanol (Ref: Molander, Gary A.;Shakya, Sagar R.; J. Org. Chem.; EN; 59; 12; 1994; 3445–3452.) (182 mg,0.69 mmol) and 4-fluoro-7-hydroxy-benzo[b]thiophene-2-carbonitrile (112mg, 0.58 mmol) in dry THF (12 mL) under an inert atmosphere on nitrogen.The resulting suspension was allowed to stir for a further 18 hrs beforethe solvent was removed in vacuo. The residue was purified by flashchromatography with a gradient of 0–4% diethyl ether in hexane to givethe title compound as a colourless oil (0.22 g, 88%); δ_(H) (300 MHz,CDCl₃) 7.83 (1H, s, 3-ArH), 7.36–7.12 (5H, m, ArH), 6.85–6.75 (1H, m,ArH), 6.65–6.57 (1H, m, ArH), 5.40–5.30 (1H, m, CHO), 3.47–3.28 (1H, m,CH₂CHHI), 3.23–3.12 (1H, m, CH₂CHHI), 2.60–2.42 (1H, m, CHHCH₂I) and2.34–2.19 (1H, m, CHHCH₂I).

Similarly prepared was

6-{[(1S)-3-Iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

as a solid (0.29 g, 99%); δ_(H) (300 MHz, CDCl₃) 7.75–7.65 (2H, m, ArH),7.41–7.02 (7H, m, ArH), 5.39–5.29 (1H, m, CHO), 3.43–3.30 (1H, m,CH₂CHHI), 3.30–3.3.18 (1H, m, CH₂CHHI), 2.59–2.42 (1H, m, CHHCH₂I) and2.39–2.22 (1H, m, CHHCH₂I).7-{[(1S)-3-Iodo-1-phenyl-propyl]oxy}-6-fluoro-1-benzothiophene

as a solid (0.21 g, 52%); δ_(H) (300 MHz, CDCl₃) 7.42 (9H, m, ArH),5.55–5.49 (1H, m, CHO), 3.38–3.21 (1H, m, CH₂CHHI), 3.21–3.10 (1H, m,CH₂CHHI), 2.70–2.65 (1H, m, CHHCH₂I) and 2.40–2.26 (1H, m, CHHCH₂I).5-[(1S)-3-Iodo-1-phenylpropyl]oxy-1-methyl-1H-indole

as a solid (131 mg, 63%); mass spectrum (TOF): m/z=391.04 (M)7-[(1S)-3-Iodo-1-phenyl-propoxy)-benzofuran

to give the title compound (1.2 g, 85%); δ_(H) (300 MHz, CDCl₃) 7.64(1H, d, Ar), 7.44 (2H, m, Ar), 7.29 (3H, m, Ar), 7.13 (1H, m, Ar), 6.99(1H, m, Ar), 6.75 (1H, m, Ar), 6.66 (1H, m, Ar), 5.50 (1H, m, O—CH),3.47 (1H, m, CH2), 3.33 (1H, m, CH2), 2.64 (1H, m, CH2), 2.38 (1H, m,CH2).7-{[(1S)-3-Chloro-1-(2-thienyl)propyl]oxy}-1-benzothiophene

4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (329 mg, 0.799 mmol) was added in one portion to a stirredsolution of (1R)-3-chloro-1-(2-thienyl)-1-propanol (92 mg, 0.533 mmol)and 7-hydroxybenzo[b]thiophene (80 mg, 0.533 mmol) in dry THF (5 mL)under an inert atmosphere on nitrogen. The resulting suspension wasallowed to stir for a further 18 hrs before the solvent was removed invacuo. The residue was triturated with hexane (ca. 15 mL) and the solidfiltered, the filtrate was concentrated in vacuo and the resulting paleyellow oil was purified by flash chromatography eluting silica gel withhexane:ether [95:5] to yield the title compound as a colourless oil (35mg, 21%); R_(f)=0.78 in hexane:ether [10:1]; δ_(H) (300 MHz, CDCl₃)7.52–6.80 (9H, m, Ar), 5.95–5.88 (1H, m, CHO), 3.90–3.79 (1H, m, CHH),3.70–3.58 (1H, m, CHH), 2.80–2.65 (1H, m, CHH), 2.55–2.30 (1H, m, CHH)

7-[(1R)-3-Chloro-1-phenylpropyl]oxy-1-benzothiophene

4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (1.15 g, 2.80 mmol) was added in one portion to a stirredsolution of (S)-(−)-3-chloro-1-phenyl-1-propanol (317 mg, 1.86 mmol) and7-hydroxybenzo[b]thiophene (280 mg, 1.86 mmol) in dry THF (5 mL) underan inert atmosphere on nitrogen. The resulting suspension was allowed tostir for a further 18 hrs before the solvent was removed in vacuo. Theresidue was triturated with hexane (ca. 15 mL) and the solid filtered,the filtrate was concentrated in vacuo and the resulting pale yellow oilwas purified by flash chromatography eluting silica gel withhexane:ether [95:5] to yield the title compound as a colourless oil (240mg, 43%); R_(f)=0.78 in hexane:ether [10:1]; δ_(H) (300 MHz, CDCl₃)7.66–7.00 (9H, m, Ar); 6.55 (1H, d, Ar), 5.80–5.72 (1H, m, CHO),3.91–3.60 (2H, m, CH₂), 2.62–2.50 (1H, m, CHH), 2.38–2.22 (1H, m, CHH).

Similarly prepared were

4-[(1R)-3-Chloro-1-phenylpropyl]oxy-1-benzothiophene as a colourless oil

(104 mg 52%); δ_(H) (300 MHz, CDCl₃) 7.59–7.01 (9H, m, Ar); 6.55 (1H, d,Ar), 5.60–5.42 (1H, m, CHO), 3.84–3.70 (1H, m, CHH), 3.68–3.52 (1H, m,CHH), 2.62–2.48 (1H, m, CHH), 2.35–2.29 (1H, m, CHH).5-[(1R)-3-Chloro-1-phenylpropyl]oxy-1-benzothiophene (from1-benzothiophen-5-ol Ref: Perez-Silanes, S.; Martinez-Esparza, J.;Oficialdegui, A. M.; Villanueva, H.; Orus, L.; Monge, A; J. HeterocyclicChem. 2001, 38(5) 1025) as a colourless oil (540 mg, 89%); δ_(H) (300MHz, CDCl₃) 7.55 (1H, d, Ar), 7.65–6.81 (9H, m, Ar), 5.37–5.25 (1H, m,CHO), 3.79–3.65 (1H, m, CHH), 3.60–3.50 (1H, m, CHH), 2.48–2.32 (1H, m,CHH), 2.20–2.09 (1H, m, CHH).6-[(1R)-3-Chloro-1-phenylpropyl]oxy-1-benzothiophene (prepared from1-benzothiophen-6-ol Ref: Hansch, C.; Schmidhalter, B., J. Org. Chem.;1955, 20, 1056)

as a colourless oil (370 mg, 67%); δ_(H) (400 MHz, CDCl₃) 7.53 (1H, d,J=8.0 Hz, Ar), 7.32–7.08 (8H, m, Ar), 6.90(1H, d, J=4, 8 Hz, Ar), 5.34(1H, dd, J=4, 12 Hz, CHO), 3.79–3.72 (1H, m, CHH), 3.58–3.52 (1H, m,CHH), 2.46–2.37 (1H, m, CH H), 2.20–2.12 (1H, m, CHH).7-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-4-fluoro-1-benzothiophene

as a colourless oil (824 mg, 93%); δ_(H) (300 MHz, CDCl₃) 7.88–7.00 (8H,m, Ar); 6.55 (1H, d, Ar), 5.80–5.72 (1H, m, CHO), 3.91–3.60 (2H, m,CH₂), 2.62–2.50 (1H, m, CHH), 2.38–2.22 (1H, m, CHH).7-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-4-fluoro-3-methyl-1-benzothiophene.

as a colourless oil (326 mg, 81%); δ_(H) (300 MHz, CDCl₃) 7.42–7.20 (6H,m, Ar), 6.80–6.74 (1H, m, Ar), 7.45 (1H, dd, Ar), 5.58–5.48 (1H, m,CHO), 4.91–4.80 (1H, m, CHH), 4.71–4.59 (1H, m, CHH), 2.62–2.48 (4H, m,CHH and CH₃), 2.42–2.28 (1H, m, CHH).7-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-4-fluoro-3-chloro-1-benzothiophene

as a colourless oil (490 mg, 94%); δ_(H) (300 MHz, CDCl₃) 7.40–7.12 (6H,m, Ar), 6.85–6.70 (1H, m, Ar), 6.58–6.47 (1H, m, Ar), 5.55–5.45 (1H, m,CHO), 3.90–3.78 (1H, m, CHH), 3.69–3.59 (1H, m, CHH), 2.61–2.48 (1H, m,CHH), 2.32–2.19 (1H, m, CHH).7-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-4-methyl-1-benzothiophene

as a colourless oil (824 mg, 93%); δ_(H) (300 MHz, CDCl₃) 7.47–7.20 (7H,m, Ar), 6.89 (1H, d, Ar), 6.49 (1H, d, Ar), 5.59–5.50 (1H, m, CHO),3.95–3.80 (1H, m, CHH), 3.72–3.62 (1H, m, CHH), 2.62–2.41 (4H, m, CHHand CH₃), 2.32–2.20 (1H, m, CHH).7-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-2-fluoro-1-benzothiophene

as a colourless oil (370 mg, 78%); δ_(H) (300 MHz, CDCl₃) 7.45–7.02 (8H,m, Ar), 5.64–5.52 (1H, dd, Ar), 5.63–5.50 (1H, m, CHO), 3.90–3.75 (1H,m, CHH), 3.69–3.55 (1H, m, CHH), 2.62–2.48-(1H, m, CHH), 2.32–2.18 (1H,m, CHH).4-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-2-fluoro-1-benzothiophene

as a colourless oil (150 mg, 72%); δ_(H) (300 MHz, CDCl₃) 7.48–6.50 (9H,m, Ar), 5.58–5.48 (1H, m, CHO), 3.90–3.78 (1H, m, CHH), 3.70–3.58 (1H,m, CHH), 2.61–2.45-(1H, m, CHH), 2.37–2.20 (1H, m, CHH).7-[(1R)-3-Chloro-1-phenylpropyl]oxy-5-fluoro-1-benzothiophene

as a colourless oil (287 mg, 81%); R_(f)=0.5 in hexane:EtOAc [90:10];δ_(H) (300 MHz, CDCl₃) 7.48 (1H, d, Ar), 7.40–7.20 (6H, m, Ar); 7.05(1H, dd, Ar), 6.40 (1H, dd, Ar), 5.52 (1H, m, CHO), 3.91–3.60 (2H, m,CH₂), 2.62–2.20 (2H, m, CH₂).6-[(1R)-3-Chloro-1-phenylpropyl]oxy-4-trifluoromethyl-1-benzothiophene

as a pale yellow oil (265 mg, 0.715 mmol, 84%); R_(f)=0.4 inhexane:EtOAc [90:10]; δ_(H) (300 MHz, CDCl₃) 7.40–7.20 (9H, m, Ar); 5.45(1H, m, CHO), 3.90–3.55 (2H, m, CH₂), 2.60–2.15 (2H, m, CH₂).4-[(1R)-3-Chloro-1-phenylpropyl]oxy-5-fluoro-1-benzothiophene

as a colourless oil (41 mg, 67%); R_(f)=0.4 in hexane:EtOAc [90:10];δ_(H) (300 MHz, CDCl₃) 7.40–7.20 (8H, m, Ar); 7.00 (1H, t, Ar), 5.58(1H, m, CHO), 3.90–3.55 (2H, m, CH₂), 2.80–2.22 (2H, m, CH₂).4-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-7-fluoro-1-benzothiophene

as a solid (0.37 g, 95%); δ_(H) (300 MHz, CDCl₃) 7.52–7.50 (1H, m, ArH),7.35–7.15 (6H, m, ArH), 6.71–6.65 (1H, m, ArH), 6.42–6.39 (1H, m, ArH),5.42–5.36 (1H, m, CHO), 3.80–3.70 (1H, m, CH₂CHHCl), 3.61–3.51 (1H, m,CH₂CHHCl), 2.52–2.41 (1H, m, CHHCH₂Cl) and 2.28–2.13 (1H, m, CHHCH₂Cl).4-{[(1R)-3-Chloro-1-phenyl-propyl]oxy}-7-fluoro-3-methyl-1-benzothiophene

as a solid (0.34 g, 93%); δ_(H) (300 MHz, CDCl₃) 7.42–7.22 (5H, m, ArH),6.97 (1H, s, ArH), 6.70–6.68 (1H, m, ArH), 6.45–6.40 (1H, m, ArH),5.52–5.43 (1H, m, CHO), 3.83–3.75 (1H, m, CH₂CHHCl), 3.63–3.56 (1H, m,CH₂CHHCl), 2.76 (3H, s, OCH₃), 2.60–2.49 (1H, m, CHHCH₂Cl) and 2.34–2.22(1H, m, CHHCH₂Cl).7-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

as a solid (0.22 g, 71%); δ_(H) (300 MHz, CDCl₃) 7.95 (1H, s, 3-ArH),7.47–7.20 (7H, m, ArH), 6.79–6.71 (1H, m, ArH), 5.62–5.55 (1H, m, CHO),3.91–3.78 (1H, m, CH₂CHHCl), 3.69–3.58 (1H, m, CH₂CHHCl), 2.68–2.52 (1H,m, CHHCH₂Cl) and 2.49–2.25 (1H, m, CHHCH₂Cl).4-{[(1R)-3-Chloro-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

as a solid (0.17 g, 78%); δ_(H) (300 MHz, CDCl₃) 8.07 (1H, s, 3-ArH),7.35–7.17 (7H, m, ArH), 6.61–6.58 (1H, m, ArH), 5.53–5.48 (1H, m, CHO),3.80–3.68 (1H, m, CH₂CHHCl), 3.60–3.49 (1H, m, CH₂CHHCl), 2.60–2.48 (1H,m, CHHCH₂Cl) and 2.28–2.17 (1H, m, CHHCH₂Cl).4-Cyano-7-[(1R)-3-chloro-1phenylpropyl]oxy-1-benzo[b]thiophene

□_(H) (400 MHz, CDCl₃) 7.60 (1H, d, J=6 Hz), 7.48 (1H, d, J=6 Hz), 7.45(1H, d, J=8 Hz), 7.15–7.35 (5H, m), 6.58 (1H, d, J=8 Hz), 5.60 (1H, dd,J=8, 4 Hz), 3.73–3.82 (1H, m), 3.53–3.62 (1H, m), 2.49–2.60 (1H, m),2.20–2.31 (1H, m).7-[(1R)-3-Chloro-1-phenylpropyl]oxy-1-indole

as a colourless oil (103 mg, 21%); (1H NMR CDCl3) 8.42 (1H, s, NH),7.42–7.05 (8H, m, Ar), 6.82 (1H, t, Ar), 6.56–6.41 (1H, m, Ar),5.55–5.45 (1H, m, CHO), 3.91–3.80 (1H, m, CHH), 3.72–3.60 (1H, m, CHH),2.60–2.46 (1H, m, CHH), 2.32–2.20 (1H, m, CHH).4-[(1R)-3-Chloro-1-phenylpropyl]oxy-1-indole

as a colourless oil (100 mg, 47%); 8.15 (1H, s, NH), 7.45 (2H, d, Ar),7.32 (2H, t, Ar), 7.30–7.22 (1H, m, Ar), 7.15 (1H, t, Ar), 7.00–6.92(2H, m, Ar), 6.72 (1H, t, Ar), 6.35 (1H, d, Ar), 5.58–5.50 (1H, m, CHO),3.92–3.82 (1H, m, CHH), 3.72–3.62 (1H, m, CHH), 2.65–2.52 (1H, m, CHH),2.35–2.25 (1H, m, CHH).5-[(1R)-3-Chloro-1-phenylpropyl]oxy-1-methyl-1H-indole

(138 mg, 31%); mass spectrum (TOF): m/z=299.11 (M).7-{[(1R)-3-Iodo-1-Phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

To a solution7-{[(1R)-3-chloro-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile(52 mg, 0.16 mmol) in acetone (2 mL) was added sodium iodide (240 mg,1.6 mmol). This was heated to reflux for 48 h and cooled to roomtemperature, water (5 mL) was added and the aqueous layer extracted withdiethyl ether (3×5 mL). The combined organic layers were washed withbrine, dried (MgSO₄) and the solvent removed in vacuo to give a solid(66 mg, 100%) which was used without further purification; δ_(H) (300MHz, CDCl₃) 7.85 (1H, s, 3-ArH), 7.43–7.19 (7H, m, ArH), 6.81–6.78 (1H,m, ArH), 5.52–5.42 (1H, m, CHO), 3.51–3.34 (1H, m, CH₂CHHI), 3.32–3.20(1H, m, CH₂CHHI), 2.67–2.53 (1H, m, CHHCH₂I) and 2.42–2.30 (1H, m,CHHCH₂I).

Similarly prepared was

4-{[(1R)-3-Iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

as a solid (0.19 g, 90%); δ_(H) (300 MHz, CDCl₃) 8.09 (1H, s, 3-ArH),7.36–7.15 (7H, m, ArH), 6.60–6.55 (1H, m, ArH), 5.42–5.35 (1H, m, CHO),3.38–3.23 (1H, m, CH₂CHHI), 3.23–3.10 (1H, m, CH₂CHHI), 2.60–2.43 (1H,m, CHHCH₂I) and 2.39–2.22 (1H, m, CHHCH₂I).5-[(1R)-3-Iodo-1-phenylpropyl]oxy-1-methyl-1H-indole

(131 mg, 62%); mass spectrum (TOF): m/z=391.04 (M).4-Fluoro-7-{[(1R)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (498 mg, 1.12 mmol) was added in one portion to a stirredsolution of (S)-3-iodo-1-phenyl-1-propanol (Molander, Gary A.; Shakya,Sagar R.; J. Org. Chem.; 1994, 59; 12; 1994; 3445–3452) (237 mg, 0.84mmol) and 4-fluoro-7-hydroxy-benzothiophene-2-carbonitrile (144 mg, 0.70mmol) in dry THF (12 mL) under an inert atmosphere on nitrogen. Theresulting suspension was allowed to stir for a further 18 hrs before thesolvent was removed in vacuo. The residue was purified by flashchromatography with a gradient of 0–4% diethyl ether in hexane to givethe title compound as a colourless oil (284 mg, 72%); δ_(H) (300 MHz,CDCl₃) 7.83 (1H, s, 3-ArH), 7.36–7.12 (5H, m, ArH), 6.85–6.75 (1H, m,ArH), 6.65–6.57 (1H, m, ArH), 5.40–5.30 (1H, m, CHO), 3.47–3.28 (1H, m,CH₂CHHI), 3.23–3.12 (1H, m, CH₂CHHI), 2.60–2.42 (1H, m, CHHCH₂I) and2.34–2.19 (1H, m, CHHCH₂I).

Similarly prepared were

6-{[(1R)-3-Iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile

as a solid (0.23 g, 80%); δ_(H) (300 MHz, CDCl₃) 7.75–7.65 (2H, m, ArH),7.41–7.02 (7H, m, ArH), 5.39–5.29 (1H, m, CHO), 3.43–3.30 (1H, m,CH₂CHHI), 3.30–3.3.18 (1H, m, CH₂CHHI), 2.59–2.42 (1H, m, CHHCH₂I) and2.39–2.22 (1H, m, CHHCH₂I).7-{[(1R)-3-Iodo-1-phenyl-propyl]oxy}-6-fluoro-1-benzothiophene

as a solid (0.18 g, 50%); δ_(H) (300 MHz, CDCl₃) 7.42 (9H, m, ArH),5.55–5.49 (1H, m, CHO), 3.38–3.21 (1H, m, CH₂CHHI), 3.21–3.10 (1H, m,CH₂CHHI), 2.70–2.65 (1H, m, CHHCH₂I) and 2.40–2.26 (1H, m, CHHCH₂I).7-[(1R)-3-Iodo-1-phenyl-propoxy)-1-benzofuran

to give the title compound (1.4 g, 100%); δ_(H) (300 MHz, CDCl₃) 7.64(1H, d, Ar), 7.44 (2H, m, Ar), 7.29 (3H, m, Ar), 7.13 (1H, m, Ar), 6.99(1H, m, Ar), 6.75 (1H, m, Ar), 6.66 (1H, m, Ar), 5.50 (1H, m, O—CH),3.47 (1H, m, CH₂), 3.33 (1H, m, CH₂), 2.64 (1H, m, CH₂), 2.38 (1H, m,CH₂).1-Benzothiophene-7-thiol

To a cooled solution (−78° C.) of 7-bromo-1-benzothiophene (10 g, 46.8mmol) in dry THF was added sulfur (1.5 g, 46.8 mmol). A solution oftert-butyl lithium in hexane (1.7 M, 55 mL, 92 mmol) was then addeddropwise via cannular over 30 mins. The resulting suspension was allowedto stir at −78° C. for a further 30 mins before being diluted withsaturated aqueous ammonium chloride (50 mL). The reaction mixture wasallowed to warm to room temperature and extracted with diethyl ether(100 mL). The organic phase was further extracted with aqueous sodiumhydroxide solution (2 N, 2×100 mL), the base washes were collected,washed with diethyl ether (4×100 mL) and then acidified to pH 2–3 withaqueous hydrochloric (5 N). Further diethyl ether extracts weresubsequently washed with brine (4×100 mL), with the resulting organicphase being dried (MgSO₄) and the solvent evapotated in vacuo to give apale yellow oil (2.4 g, 45%). δ_(H) (300 MHz, CDCl₃) 7.7 (1H, d,S—CH═CH), 7.5 (1H, d, S—CH═CH), 7.25–7.4 (3H, m, Ar), 3.61 (1H, s, SH).

3-[Benzyl(methyl)amino]-1-phenyl-1-propanol

A solution of 3-chloro-1-phenylpropan-1-ol (2 g, 11.7 mmol),N-methylbenzylamine (2.12 g, 17.5 mmol), potassium iodide (2.6 g, 22mmol), and potassium carbonate (3.2 g, 23.4 mmol) in dimethylformamide(120 mL) was stirred at 90° C. in a reacti-vial for 16 h. After thistime the reaction was allowed to cool to room temperature. The reactionmixture was purified by an SCX-2 column eluting with Methanol followedby ammonia:methanol solution (7 N). The organics were then evaporatedand the compound taken directly onto the next step without any furtherpurification. (M⁺H+1 [256]); δ_(H) (300 MHz, CDCl₃) 7.2–7.4 (10H, m,Ar), 4.9 (1H, t, CH—OH), 3.55 (1H, d, CH ₂—Ph), 3.45 (1H, d, CH ₂—PH),2.8–3 (1H, m, CH₂), 2.55–2.65 (1H, m, CH₂), 2.25 (3H, s, CH₃), 1.8–1.9(2H, m, CH₂), 1.6 (1H, brs, OH).

1-Benzothien-7-yl(thio)-N-benzyI-N-methyl-3-phenylpropanamine

A solution of 1-benzothiophene-7-thiol (0.32 g, 1.96 mmol),3-[benzyl(methyl)amino]-1-phenyl-1-propanol (0.5 g, 1.96 mmol),(cyanomethyl) trimethylphosphonium iodide (Ref Tetrahedron, 2001, 57,5451–5454) (0.714 g, 2.94 mmol), diisopropylethylamine (0.379 g, 2.94mmol) in propionitrile (5 mL) was stirred at 90° C. in a reacti-vial for72 h. After this time the reaction was allowed to cool to roomtemperature. The reaction mixture was purified by an SCX-2 columneluting with methanol followed by ammonia:methanol solution (7 N). Theorganics were then evaporated and the compound taken directly onto thenext step without any further purification LCMS determined successfulproduct formation (M⁺H+1 [404]).

3-(1-Benzothienyl-4-yl(thio)-N-benzyl-N-methyl-3-phenyl-1-propanamine

A solution of 1-benzothiophene-4-thiol (0.32 g, 1.96 mmol),3-[benzyl(methyl)amino]-1-phenyl-1-propanol (0.5 g, 1.96 mmol),(cyanomethyl) trimethylphosphonium iodide (Ref Tetrahedron, 2001, 57,5451–5454) (0.714 g, 2.94 mmol), diisopropylethylamine (0.379 g, 2.94mmol) in propionitrile (5 mL) was stirred at 90° C. in a reacti-vial for72 h. After this time the reaction was allowed to cool to roomtemperature. The reaction mixture was purified by an SCX-2 columneluting with methanol followed by ammonia:methanol solution (7 N). Theorganics were then evaporated and the compound taken directly onto thenext step without any further purification. Product formation wasdetermined by LCMS (M⁺H+1 [404]).

In the following section, there is described the synthesis of compoundsof the present invention.

EXAMPLE 1 (3S)-3-(1-Benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

Methylamine (40% in water, 3 mL) was dissolved in a solution of7-[(1S)-3-chloro-1-phenylpropyl]oxy-1-benzothiophene (60 mg, 0.19 mmol)in ethanol (abs, 3 mL), the resulting solution was heated to 130° C. ina sealed bomb for 3 h. After this time the reaction was allowed to coolto room temperature before the solvent was removed in vacuo. The residuewas purified by flash chromatography eluting silica gel withCHCl₃:Methanol [10:1] to yield a colourless oil.

The resulting oil was dissolved in ethyl acetate (5 mL) and a solutionof oxalic acid (16 mg, 0.126 mmol) in ethyl acetate (2 mL) added. Themixture was stirred at room temperature for 10 mins and then the solventremoved in vacuo. The residue was dissolved in acetonitrile (1 mL) andwater (5 mL), this solution was then frozen by immersion in a dryice:acetone bath, the resulting frozen material was freeze driedovernight to yield the target compound as a fluffy white solid (72 mg);δ_(H) (300 MHz, CDCl₃) 7.50–7.25 (8H, m, Ar), 7.15 (1H, t, Ar), 6.55(1H, d, Ar), 5.50 (1H, bd, CHO), 3.70 (3H, s, NCH₃), 3.22 (2H, m, CH₂),2.42 (2H, m, CH₂).

Similarly prepared were

EXAMPLE 2 (3S)-3-(1-Benzothien-4-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (124 mg, 82%); δ_(H) (300 MHz, CD₃OD) 7.50–7.25 (8H, m, Ar),7.15 (1H, t, Ar), 6.55 (1H, d, Ar), 5.62–5.44 (1H, m, CHO), 3.70 (3H, s,NCH₃), 3.36–3.21 (2H, m, CH₂), 2.50–2.36 (2H, m, CH₂).

EXAMPLE 3 (3S)-3-(1-Benzothien-5-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (200 mg, 82%); δ_(H) (300 MHz, CD₃OD) 8.00–7.91 (1H, d, Ar),7.70–7.22 (9H, m, Ar), 5.70–5.60 (1H, m, CHO), 3.58 (3H, s, NCH₃),3.56–3.38 (2H, m, CH₂), 2.52–2.36 (2H, m, CH₂).

EXAMPLE 3A (3S)-3-(1-Benzothien-6-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (268 mg, 74%); δ_(H) (400 MHz, CDCl₃) 7.61 (1H, d, J=9.0 Hz,Ar), 7.39–7.16 (8H, m, Ar), 6.99 (1H, dd, J=2,8 Hz, Ar), 5.30 (1H, dd,J=5, 8 Hz, CHO), 2.81–2.78 (2H, m, CH₂), 2.45 (3H, s, NCH₃), 2.26–2.20(1H, m, CH H), 2.08–2.03 (1H, m, CH H).

EXAMPLE 4 (3S)-3-(1-Indol-7-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (89 mg, 40%); δ_(H) (300 MHz, CD₃OD) 7.40–6.92 (8H, m, Ar),6.67–6.59 (1H, t, Ar), 6.35–6.25 (1H, m, Ar), 5.51–5.40 (1H, m, CHO),3.28–3.11 (5H, m, NCH₃ and CH₂), 2.40–2.12 (2H, m, CH₂).

EXAMPLE 5 (3S)-3-(1-Indol-4-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (80 mg, 59%); δ_(H) (300 MHz, CD₃OD) 7.45 (2H, d, Ar),7.40–7.25 (3H, m, Ar), 7.18 (1H, d, Ar), 6.98 (1H, d, Ar), 6.85 (1H, t,Ar), 6.65 (1H, d, Ar), 6.32 (1H, d, Ar), 5.62–5.52 (1H, m, CHO),3.40–3.20 (2H, m, CH₂), 2.75 (3H, s, NCH₃), 2.50–2.25 (2H, m, CH₂).

EXAMPLE 6(3S)-3-(4-Fluoro-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (236 mg, 77%); δ_(H) (300 MHz, CD₃OD) 7.68–7.21 (7H, m, Ar),6.89–6.75 (1H, m, Ar), 6.67–6.55 (1H, m, Ar), 5.60–5.50 (1H, m, CHO),3.38–3.12 (5H, m, NCH₃ and CH₂), 2.52–2.20 (2H, m, CH₂).

EXAMPLE 7(3S)-3-(4-Fluoro-3-methyl-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (300 mg, 92%); δ_(H) (300 MHz, CD₃OD) 7.35–7.00 (6H, m, Ar),6.71–6.61 (1H, m, Ar), 6.52–6.42 (1H, dd, Ar), 5.50–5.40 (1H, m, CHO),3.26–3.06 (5H, m, NCH₃ and CH₂), 2.45–2.15 (5H, m, CH₃ and CH₂).

EXAMPLE 8(3S)-3-(3-Chloro-4-fluoro-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (284 mg, 60%); δ_(H) (300 MHz, CD₃OD) 7.40–7.00 (6H, m, Ar),6.71–6.61 (1H, m, Ar), 6.52–6.42 (1H, dd, Ar), 5.50–5.40 (1H, m, CHO),3.26–3.06 (5H, m, NCH₃ and CH₂), 2.45–2.15 (2H, m, CH₂).

EXAMPLE 9(3S)-3-(4-Methyl-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a colourless oil (670 mg, 76%); δ_(H) (300 MHz, CDCl₃) 7.45–7.15 (7H,m, Ar), 6.82 (1H, d, Ar), 6.42 (1H, d, Ar), 5.55–5.48 (1H, m, CHO),3.20–3.12 (2H, m, CH₂), 2.62–2.34 (4H, m, CHH and CH₃ and NCH₃).

EXAMPLE 10(3S)-3-(2-Fluoro-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

Procedure identical to above to give the title compound as a solid (220mg, 76%); δ_(H) (300 MHz, CD₃OD) 7.38–6.90 (8H, m, Ar), 6.62–6.49 (1H,m, Ar), 5.55–5.40 (1H, m, CHO), 3.29–3.16 (5H, m, NCH₃ and CH₂),2.40–2.12 (2H, m, CH₂).

EXAMPLE 11(3S)-3-(2-Fluoro-1-benzothien-4-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

Procedure identical to above to give the title compound as a solid (108mg, 86%); δ_(H) (300 MHz, CDCl₃) 7.50–7.08 (8H, m, Ar), 6.78–6.69 (1H,m, Ar), 5.69–5.59 (1H, m, CHO), 3.35–3.15 (5H, m, NCH₃ and CH₂),2.52–2.24 (2H, m, CH₂).

EXAMPLE 12(3S)-3-(5-Fluoro-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a fluffy white solid (198 mg, 0.563 mmol, 68%); δ_(H) (300 MHz,CDCl₃) 9.70 (2H, bs, NH₂ ⁺Cl⁻), 7.48 (1H, d, Ar), 7.40–7.20 (6H, m, Ar),7.02 (1H, dd, Ar), 6.40 (1H, dd, Ar), 5.50 (1H, bd, CHO), 3.18 (2H, bd,CH₂), 2.60 (3H, bt, NCH₃), 2.50 (2H, bm, CH₂).

EXAMPLE 13(3S)-3-(4-Trifluoromethyl-1-benzothien-6-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a fluffy white solid (179 mg, 0.445 mmol, 70%); δ_(H) (300 MHz,CDCl₃) 7.40–7.20 (9H, m, Ar), 5.45 (1H, m, CHO), 3.10 (2H, m, CH₂), 2.60(3H, s, NCH₃), 2.45 (2H, m, CH₂).

EXAMPLE 14(3S)-3-(5-Fluoro-1-benzothien-4-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a fluffy white solid (31 mg, 0.093 mmol, 85%); δ_(H) (300 MHz, CDCl₃)9.90–9.30 (2H, bs, NH₂ ⁺Cl⁻), 7.40–7.15 (8H, m, Ar), 7.02 (1H, t, Ar),5.50 (1H, m, CHO), 3.25 (2H, bm, CH₂), 2.68 (3H, s, NCH₃), 2.90–2.40(2H, m, CH₂).

EXAMPLE 15(3S)-3-[(7-Fluoro-1-benzothien-4-yl)oxy]-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (0.24 g, 82%); δ_(H) (300 MHz, DMSO) 9.00 (2H, br. s, NH₂ ⁺),7.85–7.80 (1H, m, ArH), 7.75–7.68 (1H, m, ArH), 7.49–7.22 (5H, m, ArH),7.09–6.97 (1H, m, ArH), 7.72–7.65 (1H, m, ArH), 5.72–5.62 (1H, m, CHO),3.12–2.98 (2H, m, 1-CH₂), 2.56 (3H, s, NHCH₃), 2.43–2.27 (1H, m, 2-CHH)and 2.26–2.11 (1H, m, 2-CHH).

EXAMPLE 16(3S)-3-[(7-Fluoro-3-methyl-1-benzothien-4-yl)oxy]-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (0.14 g, 51%); δ_(H) (300 MHz, DMSO) 9.03 (2H, br. s, NH₂ ⁺),7.50–7.22 (6H, m, ArH), 7.01–6.91 (1H, m, ArH), 7.65–7.56 (1H, m, ArH),5.71–5.61 (1H, m, CHO), 3.15–2.95 (2H, m, 1-CH₂), 2.74 (3H, s, CH₃),2.58 (3H, s, NHCH₃), 2.45–2.28 (1H, m, 2-CHH) and 2.27–2.11 (1H, m,2-CHH).

EXAMPLE 16A(3S)-3-(4-Cyano-1-benzo[b]thien-7-yloxy)-N-methyl-3-phenyl-1-propnaminehydrochloride

□_(H) (400 MHz, DMSO-D₆) 8.93 (2H, br s), 8.11 (1H, d, J=6 Hz), 7.80(1H, d, J=8 Hz), 7.52 (1H, d, J=6 Hz), 7.27–7.48 (5H, m), 6.93 (1H, d,J=8 Hz), 5.95 (1H, br, m), 2.96–3.10 (2H, m), 2.55 (3H, s), 2.36–2.45(1H, m), 2.18–2.30 (1H, m).

EXAMPLE 17(3S)-3-[(1-Benzothien-2-carbonitrile-7-yl)oxy]-N-methyl-3-phenyl-1-propanaminefumarate

To a solution of7-{[(1S)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile (222mg, 0.5 mmol) in tetrahydrofuran (2 mL) was added 40% aqueousmethylamine (0.83 mL) and the solution was stirred at room temperaturefor 16 hours. The solvent removed in vacuo and the residue purified byflash chromatography with a gradient of 0–15% methanol indichloromethane. To a solution of free base (155 mg, 0.48 mmol) inmethanol (1 mL) and added a warm solution of fumaric acid (40 mg, 0.48mmol) in methanol (1 mL). The solvent removed in vacuo, and the solidresidue triturated with diethyl ether (5 mL), then dried in a vacuumoven at 40° C. for 1 h to give the title compound (0.20 g, 85%); δ_(H)(300 MHz, DMSO) 8.40 (1H, s, 3-ArH), 7.61–7.52 (1H, m, ArH), 7.49–7.23(6H, m, ArH), 7.05–6.98 (1H, m, ArH), 6.43 (2H, s, CHCO₂H), 5.85–5.75(1H, m, CHO), 3.05–2.90 (2H, m, 1-CH₂), 2.52 (3H, s, NHCH₃) and2.46–2.07 (2H, m, 2-CH₂).

Similarly prepared was

EXAMPLE 18(3S)-3-[(1-Benzothien-2-carbonitrile-4-yl)oxy]-N-methyl-3-phenyl-1-propanaminefumarate

as a solid (0.15 g, 79%); δ_(H) (300 MHz, DMSO) 8.57 (1H, s, 3-ArH),7.65–7.60 (1H, m, ArH), 7.49–7.23 (6H, m, ArH), 6.82–6.72 (1H, m, ArH),6.60 (2H, s, CHCO₂H), 5.76–5.66 (1H, m, CHO), 3.18–3.02 (2H, m, 1-CH₂),2.62 (3H, s, NHCH₃), and 2.39–2.10 (2H, m, 2-CH₂).

EXAMPLE 19(3S)-3-[(4-Fluoro-1-benzothien-2-carbonitrile-7-yl)oxy]-N-methyl-3-phenyl-1-propanamine

4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (383 mg, 0.93 mmol) was added in one portion to a stirredsolution of (R)-3-iodo-1-phenyl-1-propanol¹ (182 mg, 0.69 mmol) and4-fluoro-7-hydroxy-benzothiophene-2-carbonitrile (112 mg, 0.58 mmol) indry THF (12 mL) under an inert atmosphere on nitrogen. The resultingsuspension was allowed to stir for a further 18 hrs before the solventwas removed in vacuo. The residue was purified by flash chromatographywith a gradient of 0–4% diethyl ether in hexane to give the titlecompound as a colourless oil (0.22 g, 88%); δ_(H) (300 MHz, CDCl₃) 7.83(1H, s, 3-ArH), 7.36–7.12 (5H, m, ArH), 6.85–6.75 (1H, m, ArH),6.65–6.57 (1H, m, ArH), 5.40–5.30 (1H, m, HO), 3.47–3.28 (1H, m,CH₂CHHI), 3.23–3.12 (1H, m, CH₂CHHI), 2.60–2.42 (1H, m, CHHCH₂I) and2.34–2.19 (1H, m, CHHCH₂I).

Similarly prepared were

EXAMPLE 20(3S)-3-[(1-Benzothien-2-carbonitrile-6-yl)oxy]-N-methyl-3-phenyl-1-propanaminedifumarate

as a solid (0.75 g, 19%); δ_(H) (300 MHz, DMSO) 8.25 (1H, s, 3-ArH),7.92–7.88 (1H, m, ArH), 7.62 (1H, s, 7-ArH), 7.49–7.15 (6H, m, ArH),6.62 (4H, s, CHCO₂H), 5.67–5.59 (1H, m, CHO), 3.15–2.99 (2H, m, 1-CH₂),2.61 (3H, s, NHCH₃) and 2.38–2.09 (2H, m, 2-CH₂).

EXAMPLE 21(3S)-3-[(6-Fluoro-1-benzothien-7-yl)oxy]-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (0.11 g, 65%); δ_(H) (300 MHz, CDCl₃) 8.98–8.71 (1H, m, NH),8.62–8.39 (1H, m, NH), 7.48–7.02 (9H, m, ArH), 5.65–5.59 (1H, m, CHO),3.52–3.38 (2H, m, 1-CH₂), 2.94–2.78 (1H, m, 2-CHH), 2.74 (3H, m, NHCH₃)and 2.62–2.48 (1H, m, 2-CHH).

EXAMPLE 221-Methyl-[3S-(1-methyl-1H-indol-5-yloxy)-3-phenyl-propyl]-aminehydrochloride

as a fluffy white solid (23 mg, 25%); Melting point of title compound:161.8° C.

EXAMPLE 23N-Methyl-[3S-(1-methyl-1H-indol-7-yloxy)-3-phenyl-propyl]-aminehydrochloride

as a solid (108 mg, 32%); Melting point of title compound: 216.4° C.

EXAMPLE 24 (3S)-3-(1-Benzothien-7-yloxy)-3-phenyl-1-propanamine oxalate

Ammonia (0.88M, 5 mL) was dissolved in a solution of7-[(1S)-3-chloro-1-phenylpropyl]oxy-1-benzothiophene (280 mg, 0.927mmol) in ethanol (abs, 4 mL), the resulting solution was heated to 130°C. in a sealed bomb for 3 h. After this time the reaction was allowed tocool to room temperature before the solvent was removed in vacuo. Theresidue was purified by flash chromatography eluting silica gel withCHCl₃:MeOH [10:1] to yield a colourless oil.

The resulting oil was dissolved in ethyl acetate (5 mL) and a solutionof oxalic acid (62 mg, 0.695 mmol) in ethyl acetate (5 mL) added. Themixture was stirred at room temperature for 10 mins and then the solventremoved in vacuo. The residue was dissolved in acetonitrile (1 mL) andwater (5 mL), this solution was then frozen by immersion in a dryice:acetone bath, the resulting frozen material was freeze driedovernight to yield the target compound as a fluffy white solid (220 mg);δ_(H) (300 MHz, DMSO) 7.60–7.15 (9H, m, Ar), 6.65 (1H, d, Ar), 5.62 (1H,m, CHOH), 3.20 (2H, m, CH₂), 2.38 (2H, m, CH₂).

Similarly prepared was

EXAMPLE 25 (3S)-3-(4-Fluoro-1-benzothien-7-yloxy)-3-phenyl-1-propanamineoxalate

Procedure identical to above to give the title compound as a solid (218mg, 66%); δ_(H) (300 MHz, CDCl₃) 7.71–7.21 (7H, m, Ar), 6.89–6.75 (1H,m, Ar), 6.67–6.55 (1H, m, Ar), 5.63–5.56 (1H, m, CHO), 3.44–3.17 (2H, m,CH₂), 2.55–2.23 (2H, m, CH₂).

EXAMPLE 26(3S)-3-(-1-Benzothien-7-yloxy)-N-methyl-3-(2-thienyl)-1-propanamineoxalate

Methylamine (40% in water, 4 mL) was dissolved in a solution of7-{[(1S)-3-chloro-1-(2-thienyl)propyl]oxy}-1-benzothiophene (350 mg,0.113 mmol) in ethanol (abs, 4 mL), the resulting solution was heated to130° C. in a sealed bomb for 3 hrs. After this time the reaction wasallowed to cool to room temperature before the solvent was removed invacuo. The residue was purified by flash chromatography eluting silicagel with CHCl₃:Methanol [10:1] to yield a colourless oil.

The resulting oil was dissolved in ethyl acetate (3 mL) and a solutionof oxalic acid (6 mg, 0.048 mmol) in ethyl acetate 2 mL) added. Themixture was stirred at room temperature for 10 mins and then the solventremoved in vacuo. The residue was dissolved in acetonitrile (1 mL) andwater (5 mL), this solution was then frozen by immersion in a dryice:acetone bath, the resulting frozen material was freeze driedovernight to yield the target compound as a fluffy white solid (26 mg);δ_(H) (300 MHz, CDCl₃) 7.55 (1H, d, Ar), 7.38–6.80 (7H, m, Ar) 5.85–5.60(1H, m, CHO), 3.02 (2H, m, CH₂), 2.50 (3H, s, CH₃), 2.45–2.28 (2H, m,CH₂).

EXAMPLE 27 (3R)-3-(1-Benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

Methylamine (40% in water, 4 mL) was dissolved in a solution of7-[(1R)-3-chloro-1-phenylpropyl]oxy-1-benzothiophene (240 mg, 0.79 mmol)in ethanol (abs, 4 mL), the resulting solution was heated to 130° C. ina sealed bomb for 3 h. After this time the reaction was allowed to coolto room temperature before the solvent was removed in vacuo. The residuewas purified by flash chromatography eluting silica gel withCHCl₃:Methanol [10:1] to yield a colourless oil.

The resulting oil was dissolved in ethyl acetate (10 mL) and a solutionof oxalic acid (93 mg, 0.75 mmol) in ethyl acetate (5 mL) added. Themixture was stirred at room temperature for 10 mins and then the solventremoved in vacuo. The residue was dissolved in acetonitrile (3 mL) andwater (25 mL), this solution was then frozen by immersion in a dryice:acetone bath, the resulting frozen material was freeze driedovernight to yield the target compound as a fluffy white solid (315 mg);δ_(H) (300 MHz, CDCl₃) 7.50–7.25 (8H, m, Ar), 7.15 (1H, t, Ar), 6.55(1H, d, Ar), 5.50 (1H, bd, CHO), 3.70 (3H, s, NCH₃), 3.22 (2H, m, CH₂),2.42 (2H, m, CH₂).

Similarly prepared were

EXAMPLE 28 (3R)-3-(1-Benzothien-4-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (104 mg, 90%); δ_(H) (300 MHz, CD₃OD) 7.50–7.25 (8H, m, Ar),7.15 (1H, t, Ar), 6.55 (1H, d, Ar), 5.62–5.44 (1H, m, CHO), 3.70 (3H, s,NCH₃), 3.36–3.21 (2H, m, CH₂), 2.50–2.36 (2H, m, CH₂).

EXAMPLE 29 (3R)-3-(1-Benzothien-5-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (500 mg, 93%); δ_(H) (300 MHz, CD₃OD) 8.00–7.91 (1H, d, Ar),7.70–7.22 (9H, m, Ar), 5.70–5.60 (1H, m, CHO), 3.58 (3H, s, NCH₃),3.56–3.38 (2H, m, CH₂), 2.52–2.36 (2H, m, CH₂).

EXAMPLE 29A(3R)-3-(1-Benzothien-6-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (188 mg, 52%); δ_(H) (400 MHz, CDCl₃) 7.61 (1H, d, J=8.0 Hz,Ar), 7.39–7.16 (8H, m, Ar), 6.98 (1H, dd, J=4, 8 Hz, Ar), 5.30 (1H, dd,J=5, 8 Hz, CHO), 2.81–2.78 (2H, m, CH₂), 2.45 (3H, s, NCH₃), 2.26–2.20(1H, m, CH H), 2.08–2.03 (1H, m, CH H).

EXAMPLE 30 (3R)-3-(1-Indol-7-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (48 mg, 22%); δ_(H) (300 MHz, CD₃OD) 7.40–6.92 (8H, m, Ar),6.67–6.59 (1H, t, Ar), 6.35–6.25 (1H, m, Ar), 5.51–5.40 (1H, m, CHO),3.28–3.11 (5H, m, NCH₃ and CH₂), 2.40–2.12 (2H, m, CH₂).

EXAMPLE 31 (3R)-3-(1-Indol-4-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (50 mg, 39%); δ_(H) (300 MHz, CD₃OD) 7.45 (2H, d, Ar),7.40–7.25 (3H, m, Ar), 7.18 (1H, d, Ar), 6.98 (1H, d, Ar), 6.85 (1H, t,Ar), 6.65 (1H, d, Ar), 6.32 (1H, d, Ar), 5.62–5.52 (1H, m, CHO),3.40–3.20 (2H, m, CH₂), 2.75 (3H, s, NCH₃), 2.50–2.25 (2H, m, CH₂).

EXAMPLE 32(3R)-3-(4-Fluoro-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanamineoxalate

as a solid (419 mg, 96%); δ_(H) (300 MHz, CD₃OD) 7.68–7.21 (7H, m, Ar),6.89–6.75 (1H, m, Ar), 6.67–6.55 (1H, m, Ar), 5.60–5.50 (1H, m, CHO),3.38–3.12 (5H, m, NCH₃ and CH₂), 2.52–2.20 (2H, m, CH₂).

EXAMPLE 33(3R)-3-(4-Fluoro-3-methyl-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (200 mg, (80%); δ_(H) (300 MHz, CD₃OD) 7.35–7.00 (6H, m, Ar),6.71–6.61 (1H, m, Ar), 6.52–6.42 (1H, dd, Ar), 5.50–5.40 (1H, m, CHO),3.26–3.06 (5H, m, NCH₃ and CH₂), 2.45–2.15 (5H, m, CH₃ and CH₂).

EXAMPLE 34(3R)-3-(3-Chloro-4-fluoro-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (340 mg, 71%); δ_(H) (300 MHz, CD₃OD) 7.40–7.00 (6H, m, Ar),6.71–6.61 (1H, m, Ar), 6.52–6.42 (1H, dd, Ar), 5.50–5.40 (1H, m, CHO),3.26–3.06 (5H, m, NCH₃ and CH₂), 2.45–2.15 (2H, m, CH₂).

EXAMPLE 35(3R)-3-(4-Methyl-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a colourless oil (824 mg, 93%); δ_(H) (300 MHz, CDCl₃) 7.45–7.15 (7H,m, Ar), 6.82 (1H, d, Ar), 6.42 (1H, d, Ar), 5.55–5.48 (1H, m, CHO),3.20–3.12 (2H, m, CH₂), 2.62–2.34 (4H, m, CHH and CH₃ and NCH₃).

EXAMPLE 36(3R)-3-(2-Fluoro-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (270 mg, 80%); δ_(H) (300 MHz, CD₃OD) 7.38–6.90 (8H, m, Ar),6.62–6.49 (1H, m, Ar), 5.55–5.40 (1H, m, CHO), 3.29–3.16 (5H, m, NCH₃and CH₂), 2.40–2.12 (2H, m, CH₂).

EXAMPLE 37(3R)-3-(2-Fluoro-1-benzothien-4-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (97 mg, 60%); δ_(H) (300 MHz, CD₃OD) 7.50–7.08 (8H, m, Ar),6.78–6.69 (1H, m, Ar), 5.69–5.59 (1H, m, CHO), 3.35–3.15 (5H, m, NCH₃and CH₂), 2.52–2.24 (2H, m, CH₂).

EXAMPLE 38(3R)-3-(5-Fluoro-1-benzothien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a fluffy white solid (165 mg, 60%); δ_(H) (300 MHz, CDCl₃) 9.70 (2H,bs, NH₂ ^(+Cl) ⁻), 7.48 (1H, d, Ar), 7.40–7.20 (6H, m, Ar), 7.02 (1H,dd, Ar), 6.40 (1H, dd, Ar), 5.50 (1H, bd, CHO), 3.18 (2H, bd, CH₂), 2.60(3H, bt, NCH₃), 2.50 (2H, bm, CH₂).

EXAMPLE 39(3R)-3-(4-Trifluoromethyl-1-benzothien-6-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a fluffy white solid (184 mg, 62%); δ_(H) (300 MHz, CDCl₃) 7.40–7.20(9H, m, Ar), 5.45 (1H, m, CHO), 3.10 (2H, m, CH₂), 2.60 (3H, s, NCH₃),2.45 (2H, m, CH₂).

EXAMPLE 40(3R)-3-(5-Fluoro-1-benzothien-4-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

as a fluffy white solid (37 mg, 89%); δ_(H) (300 MHz, CDCl₃) 8.30 (1H,bs, NH), 7.40–7.15 (8H, m, Ar), 7.02 (1H, t, Ar), 5.50 (1H, m, CHO),3.25 (2H, bm, CH₂), 2.68 (3H, s, NCH₃), 2.80–2.35 (2H, m, CH₂).

EXAMPLE 41(3R)-3-[(7-Fluoro-1-benzothien-4-yl)oxy]-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (0.20 g, 40%); δ_(H) (300 MHz, DMSO) 8.95 (2H, br. s, NH₂ ⁺),7.85–7.80 (1H, m, ArH), 7.75–7.68 (1H, m, ArH), 7.49–7.22 (5H, m, ArH),7.09–6.97 (1H, m, ArH), 7.72–7.65 (1H, m, ArH), 5.72–5.62 (1H, m, CHO),3.12–2.98 (2H, m, 1-CH₂), 2.56 (3H, s, NHCH₃), 2.43–2.27 (1H, m, 2-CHH)and 2.26–2.11 (1H, m, 2-CHH).

EXAMPLE 41A(3R)-3-[(7-Fluoro-3-methyl-1-benzothien-4-yl)oxy]-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (0.20 g, 55%); δ_(H) (300 MHz, DMSO) 8.90 (2H, br. s, NH₂ ⁺),7.50–7.22 (6H, m, ArH), 7.01–6.91 (1H, m, ArH), 7.65–7.56 (1H, m, ArH),5.71–5.61 (1H, m, CHO), 3.15–2.95 (2H, m, 1-CH₂), 2.74 (3H, s, CH₃),2.58 (3H, s, NHCH₃), 2.45–2.28 (1H, m, 2-CHH) and 2.27–2.11 (1H, m,2-CHH).

EXAMPLE 41B(3R)-3-(4-Cyano-1-benzo[b]thien-7-yloxy)-N-methyl-3-phenyl-1-propanaminehydrochloride

□_(H) (400 MHz, DMSO-D₆) 8.93 (2H, br s), 8.11 (1H, d, J=6 Hz), 7.80(1H, d, J=8 Hz), 7.52 (1H, d, J=6 Hz), 7.27–7.48 (5H, m), 6.93 (1H, d,J=8 Hz), 5.95 (1H, br m), 2.96–3.10 (2H, m), 2.55 (3H, s), 2.36–2.45(1H, m), 2.18–2.30 (1H, m).

EXAMPLE 42(3R)-3-[(1-Benzothien-2-carbonitrile-7-yl)oxy]-N-methyl-3-phenyl-1-propanaminefumarate

To a solution of7-{[(1R)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile (156mg, 0.37 mmol) in tetrahydrofuran (1.5 mL) was added 40% aqueousmethylamine (0.5 mL) and the solution was stirred at room temperaturefor 16 hours. The solvent removed in vacuo and the residue purified byflash chromatography with a gradient of 0–15% methanol indichloromethane. To a solution of free base (96 mg, 0.3 mmol) inmethanol (1 mL) and added a warm solution of fumaric acid (26 mg, 0.3mmol) in methanol (1 mL). The solvent removed in vacuo, and the solidresidue triturated with ether (5 mL), then dried in a vacuum oven at 40°C. for 1 hour to give the title compound (120 mg, 74%); δ_(H) (300 MHz,DMSO) 8.40 (1H, s, 3-ArH), 7.61–7.52 (1H, m, ArH), 7.49–7.23 (6H, m,ArH), 7.05–6.98 (1H, m, ArH), 6.45 (2H, s, CHCO₂H), 5.85–5.75 (1H, m,CHO), 3.05–2.90 (2H, m, 1-CH₂), 2.52 (3H, s, NHCH₃) and 2.46–2.07 (2H,m, 2-CH₂).

Similarly prepared were

EXAMPLE 43(3R)-3-[(1-Benzothien-2-carbonitrile-4-yl)oxy]-N-methyl-3-phenyl-1-propanaminefumarate

as a solid (0.17 g, 85%); δ_(H) (300 MHz, DMSO) 8.57 (1H, s, 3-ArH),7.65–7.60 (1H, m, ArH), 7.49–7.23 (6H, m, ArH), 6.82–6.72 (1H, m, ArH),6.60 (2H, s, CHCO₂H), 5.76–5.66 (1H, m, CHO), 3.18–3.02 (2H, m, 1-CH₂),2.62 (3H, s, NHCH₃), and 2.39–2.10 (2H, m, 2-CH₂).

EXAMPLE 44(3R)-3-[(4-Fluoro-1-benzothien-2-carbonitrile-7-yl)oxy]-N-methyl-3-phenyl-1-propanaminefumarate

as a solid (0.57 g, 22%); δ_(H) (300 MHz, DMSO) 8.51–8.42 (1H, m,3-ArH), 7.49–6.90 (7H, m, ArH), 6.52–6.41 (2H, s, CHCO₂H), 3.10–2.87(2H, m, 1-CH₂) and 2.62–2.07 (5H, m, NHCH₃ and 2-CH₂).

EXAMPLE 45(3R)-3-[(1-Benzothien-2-carbonitrile-6-yl)oxy]-N-methyl-3-phenyl-1-propanaminedifumarate

as a solid (0.78 g, 26%); δ_(H) (300 MHz, DMSO) 13.12 (8H, br. s, CO₂H),8.24 (1H, s, 3-ArH), 7.92–7.88 (1H, m, ArH), 7.61 (1H, s, 7-ArH),7.49–7.15 (6H, m, ArH), 6.62 (4H, s, CHCO₂H), 5.66–5.58 (1H, m, CHO),3.15–2.97 (2H, m, 1-CH₂), 2.60 (3H, s; NHCH₃) and 2.38–2.05 (2H, m,2-CH₂).

EXAMPLE 46(3R)-3-[(6-Fluoro-1-benzothien-7-yl)oxy]-N-methyl-3-phenyl-1-propanaminehydrochloride

as a solid (0.14 g, 90%); δ_(H) (300 MHz, CDCl₃) 9.02–8.73 (1H, m, NH),8.62–8.35 (1H, m, NH), 7.45–7.00 (9H, m, ArH), 5.62–5.54 (1H, m, CHO),3.52–3.34 (2H, m, 1-CH₂), 2.94–2.78 (1H, m, 2-CHH), 2.73 (3H, m, NHCH₃)and 2.60–2.45 (1H, m, 2-CHH).

EXAMPLE 471-Methyl-[3R-(1-methyl-1H-indol-5-yloxy)-3-phenyl-propyl]aminehydrochloride

as a solid (46 mg, 19%); Melting point: 95.4° C.

EXAMPLE 48 [3R-(Benzofuran-4-yloxy)-3-phenyl-propyl]-N-methylaminehydrochloride

4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (800 mg, 2.03 mmol) was added in one portion to a stirredsolution of (S)-(−)-3-iodo-1-phenyl-1-propanol (670 mg, 2.5 mmol) andbenzofuran-4-ol (Synth Commun, 16 (13) pg. 1635–40, 1986) (228 mg, 1.7mmol) in dry THF (5 mL) under an inert atmosphere of nitrogen. Theresulting suspension was allowed to stir for a further 24 h whileheating at 40° C. before the solvent was removed in vacuo. The residuewas taken up in CH₂Cl₂ and washed with 0.5 N NaOH. The organic phase wasdried (MgSO₄) and concentrated in vacuo. The residue was purified byflash chromatography eluting silica gel with hexane:ethyl acetate [100:0to 3:1] to yield the iodo compound (291 mg, 45%); Mass spectrum (ionspray): m/z=379.1 (M+1)

The iodo compound was directly placed, without further purification, ina solution of methylamine (2M in THF, 15 mL). The resulting solution washeated to 40° C. in a sealed tube for 4 h. After this time the reactionwas allowed to cool to room temperature before the solvent was removedin vacuo. The residue was purified by flash chromatography elutingsilica gel with CH₂Cl₂:MeOH (2M NH₃) [100:0 to 5:1] to yield thehydroiodide salt of the title compound. This white solid was dissolvedin CH₂Cl₂ and washed with 0.5 N NaOH. The aqueous phase was extracted 2times with a solution of 3:1 CHCl₃:IPA. The combined organic phase wasdried (MgSO₄), filtered and concentrated in vacuo to yield the free baseof the title compound (104.7 mg, 86%). The residue was placed in MeOH (5mL) and NH₄Cl (19.9 mg) was added. The mixture was sonicated at roomtemperature for 10 min and then the solvent removed in vacuo. Theresidue was dissolved in MeCN (0.5 mL) and water (1 mL), this solutionwas then frozen by immersion in a dry ice:acetone bath, the resultingfrozen material was freeze dried overnight to yield the target compoundas a fluffy white solid (23 mg); Melting point of title compound: 140.5°C.

Similarly prepared was

EXAMPLE 49 [3S-(Benzofuran-4-yloxy)-3-phenyl-propyl]-N-methylaminehydrochloride

A method similar to Example 3b, using (R)-(+)-3-iodo-1-phenyl-1-propanolgave the title compound (111.4 mg, 77.5%); Melting point: 138.2° C.

EXAMPLE 50 [3S-(Benzofuran-7-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

Methylamine (40% in water) (10 mL) was added to a solution of7-[(1S)-3-iodo-1-phenyl-propoxy)-benzofuran (1.00 g, 2.6 mmol) in EtOH(8 mL), the resulting solution was heated to 110° C. in a sealed tubefor 3 h. After this time the reaction was allowed to cool to roomtemperature and diluted with CH₂Cl₂ and washed with 0.5 N NaOH. Theaqueous phase was extracted 2 times with a solution of 3:1 CHCl₃:IPA.The combined organic solution was dried (MgSO₄) and concentrated invacuo. The residue was purified by flash chromatography eluting silicagel with CH₂Cl₂:MeOH (2M NH₃) [100:0 to 3:1] to yield the free-base ofthe title compound (340 mg, 46%). The resulting residue was dissolved inMeOH (5 mL) and NH₄Cl (64.6 mg) was added. The mixture was sonicated atroom temperature for 10 mins and then the solvent removed in vacuo. Theresidue was dissolved in MeCN (0.5 mL) and water (1 mL), this solutionwas then frozen by immersion in a dry ice: acetone bath, the resultingfrozen material was freeze dried overnight to yield the target compoundas a fluffy white solid; Melting Point of title compound: 60.1° C.

EXAMPLE 51 [3R-(Benzofuran-7-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

as a soluid (335 mg, 42%); Melting point of title compound: 55.7° C.

EXAMPLE 52 (3R)-3-(1-Benzothien-7-yloxy)-3-phenyl-1-propanamine oxalate

Ammonia (0.880, 4 mL) was dissolved in a solution of7-[(1R)-3-chloro-1-phenylpropyl]oxy-1-benzothiophene (240 mg, 0.79 mmol)in ethanol (abs, 4 mL), the resulting solution was heated to 130° C. ina sealed bomb for 3 h. After this time the reaction was allowed to coolto room temperature before the solvent was removed in vacuo. The residuewas purified by flash chromatography eluting silica gel with CHCl₃:MeOH[10:1] to yield a colourless oil.

The resulting oil was dissolved in ethyl acetate (10 mL) and a solutionof oxalic acid (93 mg, 0.75 mmol) in ethyl acetate (5 mL) added. Themixture was stirred at room temperature for 10 mins and then the solventevaporated in vacuo. The residue was dissolved in acetonitrile (3 mL)and water (25 mL), this solution was then frozen by immersion in a dryice:acetone bath, the resulting frozen material was freeze driedovernight to yield the target compound as a fluffy white solid (315 mg);δ_(H) (300 MHz, CDCl₃) 7.50–7.25 (8H, m, Ar), 7.15 (1H, t, Ar), 6.55(1H, d, Ar), 5.50 (1H, bd, CHO), 3.30–3.20 (2H, m, CH₂), 2.48–2.40 (2H,m, CH₂).

Similarly prepared was

EXAMPLE 53 (3R)-3-(4-Fluoro-1-benzothien-7-yloxy)-3-phenyl-1-propanamineoxalate

as a solid (296 mg, 60%); δ_(H) (300 MHz, CDCl₃) 7.71–7.21 (7H, m, Ar),6.89–6.75 (1H, m, Ar), 6.67–6.55 (1H, m, Ar), 5.63–5.56 (1H, m, CHO),3.44–3.17 (2H, m, CH₂), 2.55–2.23 (2H, m, CH₂).

The compounds of Examples 54–60 were prepared by solid phase synthesisas described herein.

ArgoPore™ is obtainable from Argonaut Technologies. The process may berun in a combinatorial fashion such that all possible compounds fromsets of precursors X—CO—CH₃ and Y—OH may be prepared. The sequence isperformed without characterisation of the resin-bound intermediates.

-   -   i) A suspension of ArgoPore-Cl (5.0 g, 5.8 mmoles) in        methylamine in THF (2 M, 50 mL, 100 mmoles) was agitated gently        for 48 hrs. The reaction mixture was filtered, and the resin        washed with THF (2×50 mL), DMF (3×50 mL) and MeOH (3×50 mL ) and        dried in vacuo at 45° C.    -   ii) Aliquots (157 mg, 0.182 mmoles) of the resin prepared in        step i were dispensed into a Bohdan MiniBlock Synthesiser        (Mettler Toledo Ltd) fitted with 10 mL reaction tubes. To each        was added a 1.25M solution of a substituted acetophenone in        isopropanol (3.65 mL, 4.56 mmoles), a 37% solution of        formaldehyde in water (0.4 mL, 4.93 mmoles) and 2M HCl in        isopropanol (0.2 mL, 1.0 mmole). The reactions were heated at        80° with orbital shaking for 18 hrs, and then cooled to RT,        filtered and washed with MeOH (3×5 mL), 20% diisopropylamine in        MeOH (5 mL), MeOH (2×5 mL) and EtOH (4×5 mL).    -   iii) To each resin was added a 1M solution of sodium borohydride        in EtOH/triethyleneglycol dimethyl ether (1/1) (4 mL, 4 mmoles).        The reactions were agitated by orbital shaking for 5 hrs, then        filtered and washed with EtOH (2×5 mL), MeOH (3×5 mL) and dry        THF (4×5 mL).    -   iv) To each resin was added a 1.81M solution of        7-hydroxybenzo[b]thiophene in 0.72M triphenylphosphine/THF (2.0        mL, 3.62 and 0.74 mmoles respectively) and a 0.97M solution of        di-tert. butyl azidodicarboxylate in THF (1.5 mL, 1.46 mmoles).        The reactions were agitated by orbital shaking for 41 hrs, the        filtered and washed with THF (3×5 mL), DMF (3×5 mL) and THF (4×5        mL).    -   v) To a suspension of each resin in dry THF (2 mL) was added        1-choroethyl chloroformate (0.2 mL, 0.265 g,. 1.85 mmoles) and        diisopropylethylamine (0.15 mL, 0.11 g, 0.86 mmoles). The        reactions were agitated by orbital shaking for 4.5 hr, then        filtered and each resin washed with THF (2×2 mL). Appropriate        filtrates and washings were combined and volatile components        removed by vacuum evaporation. Each residue was dissolved in        MeOH (4.5 mL) and heated under reflux for 15 hr. The reactions        were cooled to RT and the solutions applied to MeOH-washed SCX-2        cartridges (1.0 g/6 mL) (Jones Chromatography). After draining        under gravity the cartridges were washed with MeOH (5 mL) and        the products then eluted using a 2M solution of ammonia in MeOH        (5 mL). Removal of volatile components by vacuum evaporation        gave the desired products as racemates in ca. 30% overall yield.

EXAMPLE 54

(3R,3S)-3-(-1-Benzothien-7-yloxy)-N-methyl-3-(4-fluorophenyl)-1-propanamine,m/e 316 [M+H], δ_(H) (300 MHz, CDCl3) 7.45 6.97 (8H, m, Ar), 6.56 (1H,d, Ar), 5.45 (1H, dd, ArCHO), 2.88–2.74 (2H, m, CH₂N), 2.44 (3H, s,NCH₃), 2.33–2.31 (1H, m, CHH), 2.10–1.99 (1H, m, CHH).

The following compounds were also prepared:

EXAMPLE 55(3R,3S)-3-(-1-Benzothien-7-yloxy)-N-methyl-3-(3-methylphenyl)-1-propanamine

m/e 312 [M+H]

EXAMPLE 56(3R,3S)-3-(-1-Benzothien-7-yloxy)-N-methyl-3-(2-fluorophenyl)-1-propanamine

m/e 316 [M+H]

EXAMPLE 57(3R,3S)-3-(-1-Benzothien-7-yloxy)-N-methyl-3-(3-fluorophenyl)-1-propanamine

m/e 316 [M+H]

EXAMPLE 58(3R,3S)-3-(-1-Benzothien-7-yloxy)-N-methyl-3-(3-methoxyphenyl)-1-propanamine

m/e 328 [M+H]

EXAMPLE 59(3R,3S)-3-(-1-Benzothien-7-yloxy)-N-methyl-3-(3-trifluoromethylphenyl)-1-propanamine

m/e 366 [M+H]

EXAMPLE 60(3R3S)-3-(-1-Benzothien-7-yloxy)-N-methyl-3-(4-trifluoromethylphenyl)-1-propanamine

m/e 366 [M+H]

Racemates were separated into their two enantiomers by chiralchromatography on a 25 cm×4.6 mm ID Chiralcel-OD column (ChiralSeparations, France) using heptane/ethanol 1:1 as the mobile phase.

EXAMPLE 61 (3R & 3S)3-(1-Benzothienyl-7-yl(thio)-N-methyl-3-phenyl-1-propanamine

To a solution of1-benzothien-7-yl(thio)-N-benzyl-N-methyl-3-phenylpropanamine (0.79 g,1.96 mmol) in dichloromethane (5 mL) was added ACE-Cl (2.1 mL, 19.6mmol) and polymer supported diethylamine (PS-DIEA) (2 g, 11.76 mmol).The solution was then shaken for 3 h at RT. The resin was then filteredoff, washed with dichloromethane (5 mL) and allowed to evaporate. Theresulting solid was dissolved in methanol (5 mL) and allowed to stir at60° C. for 72 h. After this time the reaction was allowed to cool toroom temperature. The reaction mixture was purified by an SCX-2 columneluting with methanol followed by ammonia:methanol solution (7 N). Theorganics were then evaporated to yield a racemic mixture of the titlecompound. Chiral purification using using a chiralcel, OJ column, 25cm×4.6 mmid (50% Heptane:50% Ethanol:0.2% DMEA) was then performed toyield each of the desired enantiomers. The resulting oils were dissolvedin diethyl ether (10 mL) and an aqueous solution of hydrochloric acid (2N) was added. The mixture was stirred at room temperature for 10 minsand then the solvent removed in vacuo to yield the target compounds asfluffy white solids (E1: 55 mg, E2: 60 mg; overall yield over 2 steps10%. (M⁺H+1 [314]); δ_(H) (300 MHz, CDCl₃) 7.7 (1H, d, S—C═C), 7.4 (1H,d, S—C═C), 7.3 (1H, d, Ar), 7.1–7.2 (7H, m, Ar), 4.4 (1H, t, S—CH), 2.55(2H, m, CH₂), 2.3 (3H, s, CH₃), 2.15 (2H, m, CH₂), 1.9 (1H, brs, NH).

EXAMPLE 62 (3R & 3S)3-(1-Benzothienyl-4-yl(thio)-N-methyl-3-phenyl-1-propanaminehydrochloride

To a solution of benzylated material (0.79 g, 1.96 mmol) indichloromethane (5 mL) was added ACE-Cl (2.1 mL, 19.6 mmol) and polymersupported diethylamine (PS-DIEA) (2 g, 11.76 mmol). The solution wasthen shaken for 3 h at RT. The resin was then filtered off, washed withdichloromethane (2×5 mL) and allowed to evaporate. The resulting solidwas dissolved in methanol (5 mL) and allowed to stir at 60° C. for 72 h.After this time the reaction was allowed to cool to room temperature.The reaction mixture was purified by an SCX-2 column eluting withmethanol followed by ammonia:methanol solution (7 N). The organics werethen evaporated to yield a racemic mixture of the title compound. Chiralpurification was then performed using a chiralcel, OJ column (40%Heptane: 60% IPA: 0.2% DMEA) to yield each of the desired enantiomers.The resulting oils were dissolved in diethyl ether (10 mL) and asolution of aqueous hydrochloric acid (2 N) was added. The mixture wasstirred at room temperature for 10 mins and then the solvent removed invacuo to yield the target compounds as fluffy white solids (E:1 43 mg,E2: 35 mg), overall yield over 2 steps 7%; LCMS M⁺H+1[314]); δ_(H) (300MHz, CDCl₃) 7.7 (1H, s, S—C═C), 7.5 (1H, d, S—S═C), 7.4 (1H, d, Ar),7.1–7.25 (7H, m, Ar), 4.3 (1H, t, CH), 2.8 (1H, brs, NH), 2.5–2.6 (2H,m, CH₂), 2.3 (1H, s, CH₃), 2.1–2.2 (2H, m, CH₂).

The compounds of the present invention may be used as medicaments inhuman or veterinary medicine. The compounds may be administered byvarious routes, for example, by oral or rectal routes, topically orparenterally, for example by injection, and are usually employed in theform of a pharmaceutical composition.

Such compositions may be prepared by methods well known in thepharmaceutical art and normally comprise at least one active compound inassociation with a pharmaceutically acceptable diluent or carrier. Inmaking the compositions of the present invention, the active ingredientwill usually be mixed with a carrier or diluted by a carrier, and/orenclosed within a carrier which may, for example, be in the form of acapsule, sachet, paper or other container. Where the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient or medium for the active ingredient. Thus, thecomposition may be in the form of tablets, lozenges, sachets, cachets,elixirs, suspensions, solutions, syrups, aerosol (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,injection solutions and suspensions and sterile packaged powders.

Some examples of suitable carriers are lactose, dextrose, vegetableoils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatin, carbohydrates such as starch and petroleum jelly,sucrose sorbitol, mannitol, starches, gum acacia,calcium phosphate,alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- andpropyl-hydrobenzoate, talc, magnesium stearate and mineral oil. Thecompounds of formula (I) can also be lyophilized and the lyophilizatesobtained used, for example, for the production of injectionpreparations. The preparations indicated can be sterilized and/or cancontain auxiliaries such as lubricants, preservatives, stabilizersand/or wetting agents, emulsifiers, salts for affecting the osmoticpressure, buffer substances, colourants, flavourings and/or one or morefurther active compounds, e.g. one or more vitamins.

Compositions of the invention may be formulated so as to provide, quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 5 to about 500 mg, more usually about 25 toabout 300 mg, of the active ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary doses for humansubjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

Scintillation Proximity Assays for Determining the Affinity of TestLigands at the Norepinephrine and Serotonin Transporters.

The compounds of the invention are norepinephrine and serotonin reuptakeinhibitors, and possess excellent activity in, for example, ascintillation proximity assay (e.g. J. Gobel, D. L. Saussy and A. Goetz,J. Pharmacol. Toxicolo. (1999), 42, 237–244). Thus ³H-nisoxetine bindingto norepinephrine re-uptake sites in a cell line transfected with humannorepinephrine transporter binding protein and similarly ³H-citaloprambinding to serotonin re-uptake sites in a cell line transfected withhuman serotonin transporter binding protein have been used to determinethe affinity of ligands at the norepinephrine and serotonin transportersrespectively.

Formalin Paw Assay

The analgesic effect of compounds of the invention for the treatment ofpersistent nociceptive pain was demonstrated using the well-known“formalin test.” The formalin test is a model of persistent nociceptiveactivation induced by tissue injury which can lead to centralsensitization. (Shibata, M., Ohkubo, T., Takahashi, H., and Inoki, R.,“Modified formalin test: Characteristic biphasic pain response,” Pain(1989) 38: 347–352; and Tjolsen, A., Berge, O. G., Hunskaar, S.,Rosland, J. H., and Hole, K., “The formalin test: an evaluation of themethod,” Pain (1992) 51:5–17.) The effect of compounds of the inventionon formalin-induced paw-licking behavior in the rat was investigated asan index of persistent nociceptive activation. In this test, theinjection of formalin under the skin on the dorsal lateral surface ofthe hind paw of rats causes an immediate and intense increase in thespontaneous activity of C fiber afferents. This activation evokes adistinctly quantifiable behavior indicative of pain, such as licking ofthe injected paw. The behavioral response to formalin is biphasic, withan early phase that is short lived, followed by an extended tonicresponse or late phase of persistent nociceptive activation. Mechanismscausing the late phase response, such as central sensitization of paintransmitting neurons, are currently believed to contribute to varioustypes of persistent pains.

Male Sprague-Dawley rats (200–250 g; Charles River, Portage, Mich.) weremaintained at constant temperature and light (12 h light/12 h dark) for4–7 days prior to the studies. Animals had free access to food and waterat all times prior to the day of the experiment.

The formalin test was performed in custom made Plexiglass® boxes25×25×20 cm (length×width×height) in size. A mirror placed at the backof the box allowed the unhindered observation of the formalin injectedpaw. Rats were acclimatized individually in the cubicles at least 1 hourprior to the experiment. All testing was conducted between 08:00 and14:00 hr and the testing room temperature was maintained at 21–23° C.Test compound was administered 30 or 60 minutes prior to the formalininjection. Formalin (50 μl of a 5% solution in saline) was injectedsubcutaneously into the dorsal lateral surface of the right hind pawwith a 27 gauge needle. Observation started immediately after theformalin injection. Formalin-induced pain was quantified by recording in5 minute intervals the number of formalin injected paw licking eventsand the number of seconds each licking event lasted. These recordingswere made for 50 minutes after the formalin injection. Scoring in theformalin test was performed according to Coderre et al., 1993b andAbbott et al., 1995. (Coderre T. J., Fundytus M. E., McKenna J. E.,Dalal S. and Melzack R. “The formalin test: a validation of theweighted-scores method of the behavioral pain rating,” Pain(1993b) 54:43–50; and Abbott F. V., Franklin K. B. J. and Westbrook R. F. “Theformalin test: scoring properties of the first and second phases of thepain response in rats,” Pain (1995) 60: 91–102.) The sum of time spentlicking in seconds from time 0 to 5 minutes was considered the earlyphase while the late phase was taken as the sum of seconds spent lickingfrom 15 to 40 minutes.

Data are presented as means with standard errors of means (±SEM). Datawere evaluated by one-way analysis of variance (ANOVA) and theappropriate contrasts analyzed by Tukey's test and Dunnett “t’ test fortwo-sided comparisons.

1. A compound of formula I:

wherein A is selected from —O— and —S—; X is selected from phenyloptionally substituted with up to 5 substituents selected from halo,C₁–C₄ alkyl and C₁–C₄ alkoxy; Y is selected from benzothienyl, indolyland benzofuranyl, optionally substituted with up to 5 substituentsselected from halo, C₁–C₄ alkyl, C₁–C₄ alkoxy, nitro, acetyl and cyano;and when Y is indolyl it may be substituted or further substituted by anN-substituent selected from C₁–C₄ alkyl; R₁ and R₂ are eachindependently H or C₁–C₄ alkyl; and pharmaceutically acceptable saltsthereof.
 2. A compound as claimed in claim 1, wherein A is —O—.
 3. Acompound as claimed in claim 1, wherein A is —S—.
 4. A compound asclaimed in any one of claims 1–3, wherein one of R₁ and R₂ is H.
 5. Acompound as claimed in any one of claims 1–3, wherein one of R₁ and R₂is H and the other is methyl.
 6. A compound as claimed in any one ofclaims 1–3, wherein X is unsubstituted phenyl or phenyl mono- di- ortri-substituted with halo, C₁–C₄ alkyl or C₁–C₄ alkoxy.
 7. A compound asclaimed in any one of claims 1–3, wherein Y is indolyl.
 8. A compound asclaimed in claim 7, wherein the indolyl group is N-substituted with amethyl substituent.
 9. A compound as claimed in any one of claims 1–3,wherein Y is benzofuranyl.
 10. A compound as claimed in any one ofclaims 1–3, wherein Y is benzothienyl.
 11. A compound as claimed in anyone of claims 1–3, wherein the point of attachment of the group Y to the—O— or —S— atom is attachment at the 7 position.
 12. A compound asclaimed in any one of claims 1–3, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 4 position.
 13. Acompound as claimed in any one of claims 1–3, wherein X is phenyl and Yis benzothienyl.
 14. A compound as claimed in claim 13, wherein Yhalo-substituted benzothienyl.
 15. A compound as claimed in claim 13,wherein Y is F-substituted benzothienyl.
 16. A pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof, as defined in claim 1, together with apharmaceutically acceptable diluent or carrier.
 17. A method fortreating pain, comprising administering to a patient in need thereof aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof, as defined in claim
 1. 18. A compound asclaimed in claim 4, wherein one of R₁ and R₂ is H and the other ismethyl.
 19. A compound as claimed in claim 4, wherein X is unsubstitutedphenyl or phenyl mono- di- or tri-substituted with halo, C₁–C₄ alkyl orC₁–C₄ alkoxy.
 20. A compound as claimed in claim 5, wherein X isunsubstituted phenyl or phenyl mono- di- or tri-substituted with halo,C₁–C₄ alkyl or C₁–C₄ alkoxy.
 21. A compound as claimed in claim 4,wherein Y is indolyl.
 22. A compound as claimed in claim 5, wherein Y isindolyl.
 23. A compound as claimed in claim 6, wherein Y is indolyl. 24.A compound as claimed in claim 4, wherein Y is benzofuranyl.
 25. Acompound as claimed in claim 5, wherein Y is benzofuranyl.
 26. Acompound as claimed in claim 6, wherein Y is benzofuranyl.
 27. Acompound as claimed in claim 4, wherein Y is benzothienyl.
 28. Acompound as claimed in claim 5, wherein Y is benzothienyl.
 29. Acompound as claimed in claim 6, wherein Y is benzothienyl.
 30. Acompound as claimed in claim 4, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 7 position.
 31. Acompound as claimed in claim 5, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 7 position.
 32. Acompound as claimed in claim 6, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 7 position.
 33. Acompound as claimed in claim 7, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 7 position.
 34. Acompound as claimed in claim 8, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 7 position.
 35. Acompound as claimed in claim 9, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 7 position.
 36. Acompound as claimed in claim 10, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 7 position.
 37. Acompound as claimed in claim 4, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 4 position.
 38. Acompound as claimed in claim 5,wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 4 position.
 39. Acompound as claimed in claim 6, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 4 position.
 40. Acompound as claimed in claim 7, wherein the point of attachment of thegroup Y to the —O— or —S— atom is attachment at the 4 position.
 41. Acompound as claimed in claim 4, wherein X is phenyl and Y isbenzothienyl.
 42. A compound as claimed in claim 5, wherein X is phenyland Y is benzothienyl.
 43. A compound as claimed in claim 6, wherein Xis phenyl and Y is benzothienyl.
 44. A compound as claimed in claim 10,wherein X is phenyl and Y is benzothienyl.
 45. A compound as claimed inclaim 11, wherein X is phenyl and Y is benzothienyl.
 46. A compound asclaimed in claim 12, wherein X is phenyl and Y is benzothienyl.